Pharmaceutical composition, methods for treating and uses thereof

ABSTRACT

The present invention relates to certain SGLT-2 inhibitors for treating, preventing, protecting against and/or delaying the progression of chronic kidney disease in patients, for example patients with prediabetes, type 1 or type 2 diabetes mellitus.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to certain SGLT-2 inhibitors for treating,preventing, protecting against and/or delaying the progression ofchronic kidney disease in patients, for example patients withprediabetes, type 1 or type 2 diabetes mellitus.

BACKGROUND OF THE INVENTION

Chronic kidney disease (CKD), also known as chronic renal disease, is aprogressive loss in renal function over a period of months or years. Thesymptoms of worsening kidney function are non-specific, and chronickidney disease is often diagnosed as a result of screening of peopleknown to be at risk of kidney problems.

Chronic kidney disease may be identified by a blood test, for examplefor creatinine. Higher levels of creatinine indicate a lower glomerularfiltration rate and as a result a decreased capability of the kidneys toexcrete waste products.

CKD has been classified into 5 stages, where stage 1 is kidney damagewith normal GFR (mL/min/1.73 m²) of ≧90; stage 2 is kidney damage with amild decrease in GFR (GFR 60-89); stage 3 is a moderate decrease in GFR(GFR 30-59); stage 4 is a severe decrease in GFR (GFR 15-29); and stage5 is kidney failure (GFR <15 or dialysis). Stage 5 CKD is often calledEnd Stage Renal Disease (ESRD) and is synonymous with the now outdatedterms chronic kidney failure (CKF) or chronic renal failure (CRF).

Albuminuria can also be a sign of kidney disease. Albuminuria has beenclassified into 3 categories, where category A1 reflects no album inuriawith albumin normal to mildly increased; category A2 which reflectsmicroalbuminuria with albumin moderately increased; category A3 whichreflects macroalbuminuria with albumin severely increased.

There is no specific treatment unequivocally shown to slow the worseningof chronic kidney disease and severe CKD requires renal replacementtherapy, which may involve a form of dialysis, but ideally constitutes akidney transplant.

Therefore, there is an unmet medical need for methods, medicaments andpharmaceutical compositions able to slow the worsening or progression ofchronic kidney disease in patients, in particular patients at risk ofrenal diseases, for example patients with prediabetes, type 1 or type 2diabetes mellitus.

SUMMARY OF THE INVENTION

Accordingly, in one aspect, the present invention relates to certainSGLT-2 inhibitors, for example empagliflozin, for treating, preventing,protecting against, reducing the risk of, delaying the occurrence ofand/or delaying the progression of chronic kidney disease in patients,for example patients with prediabetes, type 1 or type 2 diabetesmellitus.

In one embodiment, the present invention provides a method of treating,preventing, protecting against, reducing the risk of, delaying theoccurrence of and/or delaying the progression of chronic kidney diseasein a patient, said method comprising administering empagliflozin,optionally in combination with one or more other therapeutic substances,to the patient. In one aspect, the progression of said chronic kidneydisease is the progression to end stage renal disease/kidney failure, orrenal death in the patient.

In one embodiment, the present invention provides a method of treating,preventing, protecting against or delaying new onset of albuminuria in apatient, said method comprising administering empagliflozin, optionallyin combination with one or more other therapeutic substances, to thepatient. In one aspect, the patient is at risk for renal disease.

In one aspect, in one of the above methods, the patient is a patientwith prediabetes, type 1 or type 2 diabetes mellitus. In one aspect, thepatient has or is at risk of a cardiovascular disease. In one aspect,the patient is a patient with prediabetes, type 1 or type 2 diabetesmellitus and with or at risk of a cardiovascular disease.

In one embodiment, the present invention provides a method of treating,preventing, protecting against or delaying the progression from noalbuminuria to micro- or macroalbuminuria in a patient at risk for renaldisease, said method comprising administering empagliflozin, optionallyin combination with one or more other therapeutic substances, to thepatient.

In one embodiment, the present invention provides a method of treating,preventing, protecting against or delaying the progression frommicroalbuminuria to macroalbuminuria in a patient with chronic kidneydisease, said method comprising administering empagliflozin, optionallyin combination with one or more other therapeutic substances, to thepatient.

In one aspect, in a method above the patient is a patient withprediabetes, type 1 or type 2 diabetes mellitus.

In one embodiment, the present invention provides a method for treating,preventing, protecting against or delaying the progression of chronickidney disease in a patient, in particular a patient with chronic kidneydisease, said method administering empagliflozin, optionally incombination with one or more other therapeutic substances, to thepatient. In one aspect, the method is for preventing, protecting againstor delaying loss of eGFR, for example sustained eGFR loss of ≧50%, insaid patient. In one aspect, the patient is a patient with prediabetes,type 1 or type 2 diabetes mellitus.

In one embodiment, the present invention provides a method of treating,preventing, protecting against or delaying the occurrence of:

-   -   new onset of albuminuria,    -   doubling of serum creatinine level accompanied by an eGFR (based        on modification of diet in renal disease (MDRD) formula) ≦45        mL/min/1.73 m²,    -   need for continuous renal replacement therapy, or    -   death due to renal disease,    -   in a patient, said method comprising administering        empagliflozin, optionally in combination with one or more other        therapeutic substances, to the patient.

In one aspect, the patient has chronic kidney disease. In one aspect,the patient is a patient with prediabetes, type 1 or type 2 diabetesmellitus. In one aspect, the patient has or is at risk of acardiovascular disease. In one aspect, the patient is a patient withprediabetes, type 1 or type 2 diabetes and with or at risk of acardiovascular disease. In one aspect, the patient has chronic kidneydisease and is a patient with prediabetes, type 1 or type 2 diabetesmellitus.

In one aspect, in any one of the methods above the patient is a patientwith one or more cardiovascular risk factors selected from A), B), C)and D), for example a patient with type 1 or type 2 diabetes mellitus orwith pre-diabetes with one or more cardiovascular risk factors selectedfrom A), B), C) and D):

A) previous or existing vascular disease selected from myocardialinfarction, coronary artery disease, percutaneous coronary intervention,coronary artery by-pass grafting, ischemic or hemorrhagic stroke,congestive heart failure, and peripheral occlusive arterial disease,B) advanced age >/=60-70 years, andC) one or more cardiovascular risk factors selected from

-   -   advanced type 1 or type 2 diabetes mellitus >10 years duration,    -   hypertension,    -   current daily cigarette smoking,    -   dyslipidemia,    -   obesity,    -   age >/=40,    -   metabolic syndrome, hyperinsulinemia or insulin resistance, and    -   hyperuricemia, erectile dysfunction, polycystic ovary syndrome,        sleep apnea, or family history of vascular disease or        cardiomyopathy in first-degree relative;        D) one or more of the following:    -   confirmed history of myocardial infarction,    -   unstable angina with documented multivessel coronary disease or        positive stress test,    -   multivessel Percutaneous Coronary Intervention,    -   multivessel Coronary Artery By-pass Grafting (CABG),    -   history of ischemic or hemorrhagic stroke,    -   peripheral occlusive arterial disease.

In one aspect of the present invention, a patient having cardiovasculardisease is defined as having at least one of the following:

-   -   Confirmed history of myocardial infarction; or    -   Evidence of multivessel coronary artery disease, in 2 or more        major coronary arteries, irrespective of the revascularization        status, i.e.        -   a) Either the presence of a significant stenosis (imaging            evidence of at least 50% narrowing of the luminal diameter            measured during a coronary angiography or a multi-sliced            computed tomography angiography), in 2 or more major            coronary arteries,        -   b) Or a previous revascularisation (percutaneous            transluminal coronary angioplasty with or without stent, or            coronary artery bypass grafting), in 2 or more major            coronary arteries,        -   c) Or the combination of previous revascularisation in one            major coronary artery (percutaneous transluminal coronary            angioplasty with or without stent, or coronary artery bypass            grafting), and the presence of a significant stenosis in            another major coronary artery (imaging evidence of at least            50% narrowing of the luminal diameter measured during a            coronary angiography or a multi-sliced computed tomography            angiography),            -   Note: A disease affecting the left main coronary artery                is considered as a 2-vessel disease.    -   Evidence of a single vessel coronary artery disease with:        -   a) The presence of a significant stenosis i.e. the imaging            evidence of at least 50% narrowing of the luminal diameter            of one major coronary artery in patients not subsequently            successfully revascularised (measured during a coronary            angiography or a multi-sliced computed tomography            angiography)        -   b) And at least one of the following (either (i) or (ii)):            -   i. A positive non invasive stress test, confirmed by                either:                -   1. A positive exercise tolerance test in patients                    without a complete left bundle branch block,                    Wolff-Parkinson-White syndrome, or paced ventricular                    rhythm, or                -   2. A positive stress echocardiography showing                    regional systolic wall motion abnormalities, or                -   3. A positive scintigraphic test showing                    stress-induced ischemia, i.e. the development of                    transient perfusion defects during myocardial                    perfusion imaging;            -   ii. Or patient discharged from hospital with a                documented diagnosis of unstable angina within 12 months                prior to selection.    -   Episode of unstable angina with confirmed evidence of coronary        multivessel or single vessel disease as defined above.    -   History of ischemic or haemorrhagic stroke    -   Presence of peripheral artery disease (symptomatic or not)        documented by either: previous limb angioplasty, stenting or        bypass surgery; or previous limb or foot amputation due to        circulatory insufficiency; or angiographic evidence of        significant (>50%) peripheral artery stenosis in at least one        limb; or evidence from a non-invasive measurement of significant        (>50% or as reported as hemodynamically significant) peripheral        artery stenosis in at least one limb; or ankle brachial index of        <0.9 in at least one limb.

In one aspect of the present invention, a patient having cardiovasculardisease is defined as having at least one of the following:

-   -   a) Confirmed history of myocardial infarction,    -   b) Unstable angina with documented multivessel coronary disease        (at least two major coronary arteries in angiogram) or positive        stress test (ST segment depression >=2 mm or a positive nuclear        perfusion scintigram),    -   c) Multivessel Percutaneous Coronary Intervention (PCI),    -   d) Multivessel Coronary Artery By-pass Grafting (CABG),        including with recurrent angina following surgery,    -   e) History of ischemic or hemorrhagic stroke,    -   f) Peripheral occlusive arterial disease (previous limb bypass        surgery or percutaneous transluminal angioplasty; previous limb        or foot amputation due to circulatory insufficiency,        angiographic or imaging detected (for example: ultrasound,        Magnetic Resonance Imaging) significant vessel stenosis of major        limb arteries).

In one aspect, in any one of the methods above the one or more othertherapeutic substances are selected from other antidiabetic substances.

In one aspect, any one of the methods above comprises administeringempagliflozin in combination with metformin, with linagliptin or withmetformin and linagliptin.

In one aspect, in any one of the methods above the one or more othertherapeutic substances is a RAAS inhibitor. In one aspect, the one ormore other therapeutic substances is a direct renin inhibitor, anAngiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB).

In one aspect, any one of the methods above comprises administeringempagliflozin in combination with a RAAS inhibitor. In one aspect, anyone of the methods above comprises administering empagliflozin incombination with a direct renin inhibitor, an Angiotensin-ConvertingEnzyme (ACE) inhibitor and/or an angiotensin II receptor blocker (ARB).

In one aspect, in any one of the methods above empagliflozin isadministered orally in a total daily amount of 10 mg or 25 mg. In oneaspect empagliflozin is administered as a pharmaceutical compositioncomprising 10 mg or 25 mg of empagliflozin.

In one aspect of the present invention, in a method or use disclosedherein a patient is a patient with type 2 diabetes mellitus (or type 2diabetes patient), a patient treated for type 2 diabetes mellitus, apatient diagnosed with type 2 diabetes mellitus or a patient in need oftreatment for type 2 diabetes mellitus. In one aspect, a patient is apatient with pre-diabetes.

In one aspect of the present invention, in a method or use disclosedherein a patient is a patient with obesity-related Glomerulopathy, apatient with perihilar fokal-segmental glomerulosclerosis or a patientwith IgA nephropathy.

Accordingly, in one embodiment, the present invention provides a methodof treating, preventing, protecting against, reducing the risk of,delaying the occurrence of and/or delaying the progression of chronickidney disease in a patient with obesity-related Glomerulopathy, in apatient with perihilar fokal-segmental glomerulosclerosis or in apatient with IgA nephropathy.

The present invention further provides for empagliflozin or apharmaceutical composition comprising empagliflozin for use as amedicament in any one of the methods described herein.

The present invention further provides for empagliflozin in combinationwith one or more other therapeutic substances, for example selected fromother antidiabetic substances, in particular metformin, linagliptin ormetformin and linagliptin, or a pharmaceutical composition comprisingempagliflozin and one or more other therapeutic substances, for exampleselected from other antidiabetic substances, in particular metformin,linagliptin or metformin and linagliptin, for use as a medicament in anyone of the methods described herein.

The present invention further provides for empagliflozin in combinationwith a RAAS inhibitor, in particular a direct renin inhibitor, anAngiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB), or a pharmaceutical composition comprisingempagliflozin and a RAAS inhibitor, in particular a direct renininhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/or anangiotensin II receptor blocker (ARB), for use as a medicament in anyone of the methods described herein.

The present invention further provides for empagliflozin or apharmaceutical composition comprising empagliflozin for use in thetreatment of any one of the diseases or conditions described herein.

The present invention further provides for empagliflozin in combinationwith one or more other therapeutic substances, for example selected fromother antidiabetic substances, in particular metformin, linagliptin ormetformin and linagliptin, or a pharmaceutical composition comprisingempagliflozin and one or more other therapeutic substances, for exampleselected from other antidiabetic substances, in particular metformin,linagliptin or metformin and linagliptin, for use in the treatment ofany one of the diseases or conditions described herein.

The present invention further provides for empagliflozin in combinationwith a RAAS inhibitor, in particular a direct renin inhibitor, anAngiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB), or a pharmaceutical composition comprisingempagliflozin and a RAAS inhibitor, in particular a direct renininhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/or anangiotensin II receptor blocker (ARB), for use in the treatment of anyone of the diseases or conditions described herein.

The present invention further provides for empagliflozin or apharmaceutical composition comprising empagliflozin for use in themanufacture of a medicament for use in any one of the methods describedherein.

The present invention further provides for empagliflozin in combinationwith one or more other therapeutic substances, for example selected fromother antidiabetic substances, in particular metformin, linagliptin ormetformin and linagliptin, or a pharmaceutical composition comprisingempagliflozin and one or more other therapeutic substances, for exampleselected from other antidiabetic substances, in particular metformin,linagliptin or metformin and linagliptin, for use in the manufacture ofa medicament for use in any one of the methods described herein.

The present invention further provides for empagliflozin in combinationwith a RAAS inhibitor, in particular a direct renin inhibitor, anAngiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB), or a pharmaceutical composition comprisingempagliflozin and a RAAS inhibitor, in particular a direct renininhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/or anangiotensin II receptor blocker (ARB), for use in the manufacture of amedicament for use in any one of the methods described herein.

DEFINITIONS

The term “active ingredient” of a pharmaceutical composition accordingto the present invention means the SGLT2 inhibitor according to thepresent invention. An “active ingredient” is also sometimes referred toherein as an “active substance”.

The term “body mass index” or “BMI” of a human patient is defined as theweight in kilograms divided by the square of the height in meters, suchthat BMI has units of kg/m².

The term “overweight” is defined as the condition wherein the individualhas a BMI greater than or 25 kg/m² and less than 30 kg/m². The terms“overweight” and “pre-obese” are used interchangeably.

The terms “obesity” or “being obese” and the like are defined as thecondition wherein the individual has a BMI equal to or greater than 30kg/m². According to a WHO definition the term obesity may be categorizedas follows: the term “class I obesity” is the condition wherein the BMIis equal to or greater than 30 kg/m² but lower than 35 kg/m²; the term“class II obesity” is the condition wherein the BMI is equal to orgreater than 35 kg/m² but lower than 40 kg/m²; the term “class IIIobesity” is the condition wherein the BMI is equal to or greater than 40kg/m².

The indication obesity includes in particular exogenic obesity,hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity,hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity,symptomatic obesity, infantile obesity, upper body obesity, alimentaryobesity, hypogonadal obesity, central obesity, visceral obesity,abdominal obesity.

The term “visceral obesity” is defined as the condition wherein awaist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 inwomen is measured. It defines the risk for insulin resistance and thedevelopment of pre-diabetes.

The term “abdominal obesity” is usually defined as the condition whereinthe waist circumference is >40 inches or 102 cm in men, and is >35inches or 94 cm in women. With regard to a Japanese ethnicity orJapanese patients abdominal obesity may be defined as waistcircumference ≧85 cm in men and ≧90 cm in women (see e.g. investigatingcommittee for the diagnosis of metabolic syndrome in Japan).

The term “euglycemia” is defined as the condition in which a subject hasa fasting blood glucose concentration within the normal range, greaterthan 70 mg/dL (3.89 mmol/L) and less than 100 mg/dL (5.6 mmol/L). Theword “fasting” has the usual meaning as a medical term.

The term “hyperglycemia” is defined as the condition in which a subjecthas a fasting blood glucose concentration above the normal range,greater than 100 mg/dL (5.6 mmol/L). The word “fasting” has the usualmeaning as a medical term.

The term “hypoglycemia” is defined as the condition in which a subjecthas a blood glucose concentration below the normal range, in particularbelow 70 mg/dL (3.89 mmol/L).

The term “postprandial hyperglycemia” is defined as the condition inwhich a subject has a 2 hour postprandial blood glucose or serum glucoseconcentration greater than 200 mg/dL (11.11 mmol/L).

The term “impaired fasting blood glucose” or “IFG” is defined as thecondition in which a subject has a fasting blood glucose concentrationor fasting serum glucose concentration in a range from 100 to 125 mg/dl(i.e. from 5.6 to 6.9 mmol/l), in particular greater than 110 mg/dL andless than 126 mg/dl (7.00 mmol/L). A subject with “normal fastingglucose” has a fasting glucose concentration smaller than 100 mg/dl,i.e. smaller than 5.6 mmol/l.

The term “impaired glucose tolerance” or “IGT” is defined as thecondition in which a subject has a 2 hour postprandial blood glucose orserum glucose concentration greater than 140 mg/dl (7.78 mmol/L) andless than 200 mg/dL (11.11 mmol/L). The abnormal glucose tolerance, i.e.the 2 hour postprandial blood glucose or serum glucose concentration canbe measured as the blood sugar level in mg of glucose per dL of plasma 2hours after taking 75 g of glucose after a fast. A subject with “normalglucose tolerance” has a 2 hour postprandial blood glucose or serumglucose concentration smaller than 140 mg/dl (7.78 mmol/L).

The term “hyperinsulinemia” is defined as the condition in which asubject with insulin resistance, with or without euglycemia, has fastingor postprandial serum or plasma insulin concentration elevated abovethat of normal, lean individuals without insulin resistance, having awaist-to-hip ratio <1.0 (for men) or <0.8 (for women).

The terms “insulin-sensitizing”, “insulin resistance-improving” or“insulin resistance-lowering” are synonymous and used interchangeably.

The term “insulin resistance” is defined as a state in which circulatinginsulin levels in excess of the normal response to a glucose load arerequired to maintain the euglycemic state (Ford E S, et al. JAMA. (2002)287:356-9). A method of determining insulin resistance is theeuglycaemic-hyperinsulinaemic clamp test. The ratio of insulin toglucose is determined within the scope of a combined insulin-glucoseinfusion technique. There is found to be insulin resistance if theglucose absorption is below the 25th percentile of the backgroundpopulation investigated (WHO definition). Rather less laborious than theclamp test are so called minimal models in which, during an intravenousglucose tolerance test, the insulin and glucose concentrations in theblood are measured at fixed time intervals and from these the insulinresistance is calculated. With this method, it is not possible todistinguish between hepatic and peripheral insulin resistance.

Furthermore, insulin resistance, the response of a patient with insulinresistance to therapy, insulin sensitivity and hyperinsulinemia may bequantified by assessing the “homeostasis model assessment to insulinresistance (HOMA-IR)” score, a reliable indicator of insulin resistance(Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference ismade to methods for the determination of the HOMA-index for insulinsensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), of theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(Suppl.1): A459) and to an euglycemic clamp study. In addition, plasmaadiponectin levels can be monitored as a potential surrogate of insulinsensitivity. The estimate of insulin resistance by the homeostasisassessment model (HOMA)-IR score is calculated with the formula (GalvinP, et al. Diabet Med 1992; 9:921-8):

HOMA-IR=[fasting serum insulin (μU/mL)]×[fasting plasmaglucose(mmol/L)/22.5]

Insulin resistance can be confirmed in these individuals by calculatingthe HOMA-IR score. For the purpose of this invention, insulin resistanceis defined as the clinical condition in which an individual has aHOMA-IR score >4.0 or a HOMA-IR score above the upper limit of normal asdefined for the laboratory performing the glucose and insulin assays.

As a rule, other parameters are used in everyday clinical practice toassess insulin resistance. Preferably, the patient's triglycerideconcentration is used, for example, as increased triglyceride levelscorrelate significantly with the presence of insulin resistance.

Individuals likely to have insulin resistance are those who have two ormore of the following attributes: 1) overweight or obese, 2) high bloodpressure, 3) hyperlipidemia, 4) one or more 1^(st) degree relative witha diagnosis of IGT or IFG or type 2 diabetes.

Patients with a predisposition for the development of IGT or IFG or type2 diabetes are those having euglycemia with hyperinsulinemia and are bydefinition, insulin resistant. A typical patient with insulin resistanceis usually overweight or obese. If insulin resistance can be detected,this is a particularly strong indication of the presence ofpre-diabetes. Thus, it may be that in order to maintain glucosehomoeostasis a person needs 2-3 times as much insulin as a healthyperson, without this resulting in any clinical symptoms.

“Pre-diabetes” is a general term that refers to an intermediate stagebetween normal glucose tolerance (NGT) and overt type 2 diabetesmellitus (T2DM), also referred to as intermediate hyperglycaemia. Assuch, it represents 3 groups of individuals, those with impaired glucosetolerance (IGT) alone, those with impaired fasting glucose (IFG) aloneor those with both IGT and IFG. IGT and IFG usually have distinctpathophysiologic etiologies, however also a mixed condition withfeatures of both can exist in patients. Therefore in the context of thepresent invention a patient being diagnosed of having “pre-diabetes” isan individual with diagnosed IGT or diagnosed IFG or diagnosed with bothIGT and IFG. Following the definition according to the American DiabetesAssociation (ADA) and in the context of the present invention a patientbeing diagnosed of having “pre-diabetes” is an individual with:

a) a fasting plasma glucose (FPG) concentration <100 mg/dL [1mg/dL=0.05555 mmol/L] and a 2-hour plasma glucose (PG) concentration,measured by a 75-g oral glucose tolerance test (OGTT), ranging between140 mg/dL and <200 mg/dL (i.e., IGT); orb) a fasting plasma glucose (FPG) concentration between ≧100 mg/dL and<126 mg/dL and a 2-hour plasma glucose (PG) concentration, measured by a75-g oral glucose tolerance test (OGTT) of <140 mg/dL (i.e., IFG); orc) a fasting plasma glucose (FPG) concentration between ≧100 mg/dL and<126 mg/dL and a 2-hour plasma glucose (PG) concentration, measured by a75-g oral glucose tolerance test (OGTT), ranging between ≧140 mg/dL and<200 mg/dL (i.e., both IGT and IFG).

Patients with “pre-diabetes” are individuals being pre-disposed to thedevelopment of type 2 diabetes. Pre-diabetes extends the definition ofIGT to include individuals with a fasting blood glucose within the highnormal range ≧100 mg/dL (J. B. Meigs, et al. Diabetes 2003;52:1475-1484). The scientific and medical basis for identifyingpre-diabetes as a serious health threat is laid out in a PositionStatement entitled “The Prevention or Delay of Type 2 Diabetes” issuedjointly by the American Diabetes Association and the National Instituteof Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002;25:742-749).

The methods to investigate the function of pancreatic beta-cells aresimilar to the above methods with regard to insulin sensitivity,hyperinsulinemia or insulin resistance: An improvement of beta-cellfunction can be measured for example by determining a HOMA-index forbeta-cell function (Matthews et al., Diabetologia 1985, 28: 412-19), theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(Suppl.1): A459), the insulin/C-peptide secretion after an oralglucose tolerance test or a meal tolerance test, or by employing ahyperglycemic clamp study and/or minimal modeling after a frequentlysampled intravenous glucose tolerance test (Stumvoll et al., Eur J ClinInvest 2001, 31: 380-81).

The term “type 1 diabetes” is defined as the condition in which asubject has, in the presence of autoimmunity towards the pancreaticbeta-cell or insulin, a fasting blood glucose or serum glucoseconcentration greater than 125 mg/dL (6.94 mmol/L). If a glucosetolerance test is carried out, the blood sugar level of a diabetic willbe in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hoursafter 75 g of glucose have been taken on an empty stomach, in thepresence of autoimmunity towards the pancreatic beta cell or insulin. Ina glucose tolerance test 75 g of glucose are administered orally to thepatient being tested after 10-12 hours of fasting and the blood sugarlevel is recorded immediately before taking the glucose and 1 and 2hours after taking it. The presence of autoimmunity towards thepancreatic beta-cell may be observed by detection of circulating isletcell autoantibodies [“type 1A diabetes mellitus”], i.e., at least oneof: GAD65 [glutamic acid decarboxylase-65], ICA [islet-cell cytoplasm],IA-2 [intracytoplasmatic domain of the tyrosine phosphatase-like proteinIA-2], ZnT8 [zinc-transporter-8] or anti-insulin; or other signs ofautoimmunity without the presence of typical circulating autoantibodies[type 1B diabetes], i.e. as detected through pancreatic biopsy orimaging). Typically a genetic predisposition is present (e.g. HLA, INSVNTR and PTPN22), but this is not always the case.

The term “type 2 diabetes mellitus” or “T2DM” is defined as thecondition in which a subject has a fasting blood glucose or serumglucose concentration greater than 125 mg/dL (6.94 mmol/L). Themeasurement of blood glucose values is a standard procedure in routinemedical analysis. If a glucose tolerance test is carried out, the bloodsugar level of a diabetic will be in excess of 200 mg of glucose per dL(11.1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken onan empty stomach. In a glucose tolerance test 75 g of glucose areadministered orally to the patient being tested after 10-12 hours offasting and the blood sugar level is recorded immediately before takingthe glucose and 1 and 2 hours after taking it. In a healthy subject, theblood sugar level before taking the glucose will be between 60 and 110mg per dL of plasma, less than 200 mg per dL 1 hour after taking theglucose and less than 140 mg per dL after 2 hours. If after 2 hours thevalue is between 140 and 200 mg, this is regarded as abnormal glucosetolerance.

The term “late stage type 2 diabetes mellitus” includes patients with asecondary drug failure, indication for insulin therapy and progressionto micro- and macrovascular complications e.g. diabetic nephropathy, orcoronary heart disease (CHD).

The term “HbA1c” refers to the product of a non-enzymatic glycation ofthe haemoglobin B chain. Its determination is well known to one skilledin the art. In monitoring the treatment of diabetes mellitus the HbA1cvalue is of exceptional importance. As its production dependsessentially on the blood sugar level and the life of the erythrocytes,the HbA1c in the sense of a “blood sugar memory” reflects the averageblood sugar levels of the preceding 4-6 weeks. Diabetic patients whoseHbA1c value is consistently well adjusted by intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample), aresignificantly better protected against diabetic microangiopathy. Forexample, metformin on its own achieves an average improvement in theHbA1c value in the diabetic of the order of 1.0-1.5%. This reduction ofthe HbA1C value is not sufficient in all diabetics to achieve thedesired target range of <7% or <6.5% and preferably <6% HbA1c.

The term “insufficient glycemic control” or “inadequate glycemiccontrol” in the scope of the present invention means a condition whereinpatients show HbA1c values above 6.5%, in particular above 7.0%, evenmore preferably above 7.5%, especially above 8%.

The “metabolic syndrome”, also called “syndrome X” (when used in thecontext of a metabolic disorder), also called the “dysmetabolicsyndrome” is a syndrome complex with the cardinal feature being insulinresistance (Laaksonen D E, et al. Am J Epidemiol 2002; 156:1070-7).According to the ATP III/NCEP guidelines (Executive Summary of the ThirdReport of the National Cholesterol Education Program (NCEP) Expert Panelon Detection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III) JAMA: Journal of the American MedicalAssociation (2001) 285:2486-2497), diagnosis of the metabolic syndromeis made when three or more of the following risk factors are present:

-   -   1. Abdominal obesity, defined as waist circumference >40 inches        or 102 cm in men, and >35 inches or 94 cm in women; or with        regard to a Japanese ethnicity or Japanese patients defined as        waist circumference ≧85 cm in men and ≧90 cm in women;    -   2. Triglycerides: ≧150 mg/dL    -   3. HDL-cholesterol <40 mg/dL in men    -   4. Blood pressure ≧130/85 mm Hg (SBP ≧130 or DBP ≧85)    -   5. Fasting blood glucose ≧100 mg/dL

The NCEP definitions have been validated (Laaksonen D E, et al. Am JEpidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in theblood can also be determined by standard methods in medical analysis andare described for example in Thomas L (Editor): “Labor and Diagnose”,TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to a commonly used definition, hypertension is diagnosed ifthe systolic blood pressure (SBP) exceeds a value of 140 mm Hg anddiastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patientis diagnosed with diabetes it is currently recommended that the systolicblood pressure be reduced to a level below 130 mm Hg and the diastolicblood pressure be lowered to below 80 mm Hg.

The term “chronic kidney disease (CDK)” is defined as abnormalities ofkidney structure or function, present for more than three months, withimplications for health. CKD is classified based on cause, GFR category,and albuminuria category (CGA).

CKD has been classified into 5 stages, where stage 1 is kidney damagewith normal GFR (mL/min/1.73 m2) of 90 or above; stage 2 is kidneydamage with a mild decrease in GFR (GFR 60-89); stage 3 is a moderatedecrease in GFR (GFR 30-59); stage 4 is a severe decrease in GFR (GFR15-29); and stage 5 is kidney failure (GFR <15 or dialysis). Stage 3 hasbeen subdivided into stage 3A, which is a mild to moderate decrease inGFR (GFR 45-59), and stage 3B, which is a moderate to severe decrease inGFR (GFR 30-44).

The term “glomerular filtration rate (GFR)” is defined as the volume offluid filtered from the renal (kidney) glomerular capillaries into theBowman's capsule per unit time. It is indicative of overall kidneyfunction. The glomerular filtration rate (GFR) can be calculated bymeasuring any chemical that has a steady level in the blood, and isfreely filtered but neither reabsorbed nor secreted by the kidneys. Therate therefore measured is the quantity of the substance in the urinethat originated from a calculable volume of blood. The GFR is typicallyrecorded in units of volume per time, e.g., milliliters per minute andthe formula below can be used:

GFR=(Urine Concentration×Urine Volume)/Plasma Concentration

The GFR can be determined by injecting inulin into the plasma. Sinceinulin is neither reabsorbed nor secreted by the kidney after glomerularfiltration, its rate of excretion is directly proportional to the rateof filtration of water and solutes across the glomerular filter. Anormal value is: GFR=90-125 mL/min/1.73 m², in particular GFR=100-125mL/min/1.73 m²

Other principles to determine GFR involve measuring 51Cr-EDTA,[125I]iothalamate or iohexol.

The “estimated glomerular filtration rate (eGFR)” is defined as derivedat screening from serum creatinine values based on e.g., the ChronicKidney Disease Epidemiology Collaboration (CKD-EPI) equation, theCockcroft-Gault formula or the Modification of Diet in Renal Disease(MDRD) formula, which are all known in the art.

The term “albuminuria” is defined as a condition wherein more than thenormal amount of albumin is present in the urine. Albuminuria can bedetermined by the albumin excretion rate (AER) and/or thealbumin-to-creatine ratio (ACR) in the urine (also refered to as UACR).Albuminuria categories in CKD are defined as follows:

ACR AER (approximate equivalent) Category (mg/24 hours) (mg/mmol) (mg/g)Terms A1 <30 <3 <30 Normal to mildly increased A2 30-300 3-30 30-300Moderately increased A3 >300 >30 >300 Severely increased

Category A1 reflects no albuminuria, category A2 reflectsmicroalbuminuria, category A3 reflects macroalbuminuria. The progressionof category A1 usually leads to microalbuminuria (A2) but may alsodirectly result in macroalbuminuria (A3). Progression ofmicroalbuminuria (A2) results in macroalbuminuria (A3).

The term “empagliflozin” refers to the SGLT2 inhibitor1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneof the formula

as described for example in WO 2005/092877. Methods of synthesis aredescribed in the literature, for example WO 06/120208 and WO2011/039108. According to this invention, it is to be understood thatthe definition of empagliflozin also comprises its hydrates, solvatesand polymorphic forms thereof, and prodrugs thereof. An advantageouscrystalline form of empagliflozin is described in WO 2006/117359 and WO2011/039107 which hereby are incorporated herein in their entirety. Thiscrystalline form possesses good solubility properties which enables agood bioavailability of the SGLT2 inhibitor. Furthermore, thecrystalline form is physico-chemically stable and thus provides a goodshelf-life stability of the pharmaceutical composition. Preferredpharmaceutical compositions, such as solid formulations for oraladministration, for example tablets, are described in WO 2010/092126,which hereby is incorporated herein in its entirety.

The terms “treatment” and “treating” comprise therapeutic treatment ofpatients having already developed said condition, in particular inmanifest form. Therapeutic treatment may be symptomatic treatment inorder to relieve the symptoms of the specific indication or causaltreatment in order to reverse or partially reverse the conditions of theindication or to stop or slow down progression of the disease. Thus thecompositions and methods of the present invention may be used forinstance as therapeutic treatment over a period of time as well as forchronic therapy.

The terms “prophylactically treating”, “preventivally treating” and“preventing” are used interchangeably and comprise a treatment ofpatients at risk to develop a condition mentioned hereinbefore, thusreducing said risk.

The term “tablet” comprises tablets without a coating and tablets withone or more coatings. Furthermore the “term” tablet comprises tabletshaving one, two, three or even more layers and press-coated tablets,wherein each of the beforementioned types of tablets may be without orwith one or more coatings. The term “tablet” also comprises mini, melt,chewable, effervescent and orally disintegrating tablets.

The terms “pharmacopoe” and “pharmacopoeias” refer to standardpharmacopoeias such as the “USP 31-NF 26 through Second Supplement”(United States Pharmacopeial Convention) or the “European Pharmacopoeia6.3” (European Directorate for the Quality of Medicines and Health Care,2000-2009).

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention relates to certain SGLT-2inhibitors, for example empagliflozin, for use in treating, preventing,protecting against, reducing the risk of, delaying the occurrence ofand/or delaying the progression of chronic kidney disease in patients,for example patients with prediabetes, type 1 or type 2 diabetesmellitus.

In a further aspect, the present invention relates to certain SGLT-2inhibitors, for example empagliflozin, for use in treating, preventing,protecting against or delaying new onset of albuminuria in patients.

In a further aspect, the present invention relates to certain SGLT-2inhibitors, for example empagliflozin, for use in treating, preventing,protecting against or delaying the progression from no albuminuria tomicro- or macroalbuminuria in a patient at risk for renal disease.

In a further aspect, the present invention relates to certain SGLT-2inhibitors, for example empagliflozin, for use in treating, preventing,protecting against or delaying the progression from microalbuminuria tomacroalbuminuria in a patient with chronic kidney disease.

In a further aspect, the present invention relates to certain SGLT-2inhibitors, for example empagliflozin, for use in treating, preventing,protecting against or delaying the progression of chronic kidney diseasein a patient with chronic kidney disease.

In a further aspect, the present invention relates to certain SGLT-2inhibitors, for example empagliflozin, for use in treating, preventing,protecting against or delaying the occurrence of:

-   -   new onset of albuminuria,    -   doubling of serum creatinine level accompanied by an eGFR (based        on modification of diet in renal disease (MDRD) formula) ≦45        mL/min/1.73 m²,    -   need for continuous renal replacement therapy, or    -   death due to renal disease.

In one aspect, a patient according of the present invention is a patientwith prediabetes, type 1 or type 2 diabetes mellitus. In one aspect, apatient according to the present invention is a patient is a patient atrisk for renal disease. In one aspect, a patient according to thepresent invention is a patient with or at risk of a cardiovasculardisease. In one aspect, a patient according to the present invention isa patient with prediabetes, type 1 or type 2 diabetes mellitus and withor at risk of a cardiovascular disease.

In one aspect of the present invention, in a method or use disclosedherein a patient is a patient with obesity-related Glomerulopathy, apatient with perihilar fokal-segmental glomerulosclerosis or a patientwith IgA nephropathy.

Accordingly, in one embodiment, the present invention provides a methodof treating, preventing, protecting against, reducing the risk of,delaying the occurrence of and/or delaying the progression of chronickidney disease in a patient with obesity-related Glomerulopathy, in apatient with perihilar fokal-segmental glomerulosclerosis or in apatient with IgA nephropathy.

SGLT2 inhibitors (sodium-glucose co-transporter 2) represent a novelclass of agents that are being developed for the treatment orimprovement in glycemic control in patients with type 2 diabetes.Glucopyranosyl-substituted benzene derivative are described as SGLT2inhibitors, for example in WO 01/27128, WO 03/099836, WO 2005/092877, WO2006/034489, WO 2006/064033, WO 2006/117359, WO 2006/117360, WO2007/025943, WO 2007/028814, WO 2007/031548, WO 2007/093610, WO2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940. Theglucopyranosyl-substituted benzene derivatives are proposed as inducersof urinary sugar excretion and as medicaments in the treatment ofdiabetes.

Renal filtration and reuptake of glucose contributes, among othermechanisms, to the steady state plasma glucose concentration and cantherefore serve as an antidiabetic target. Reuptake of filtered glucoseacross epithelial cells of the kidney proceeds via sodium-dependentglucose cotransporters (SGLTs) located in the brush-border membranes inthe tubuli along the sodium gradient. There are at least 3 SGLT isoformsthat differ in their expression pattern as well as in theirphysico-chemical properties. SGLT2 is exclusively expressed in thekidney, whereas SGLT1 is expressed additionally in other tissues likeintestine, colon, skeletal and cardiac muscle. SGLT3 has been found tobe a glucose sensor in interstitial cells of the intestine without anytransport function. Potentially, other related, but not yetcharacterized genes, may contribute further to renal glucose reuptake.Under normoglycemia, glucose is completely reabsorbed by SGLTs in thekidney, whereas the reuptake capacity of the kidney is saturated atglucose concentrations higher than 10 mM, resulting in glucosuria(“diabetes mellitus”). This threshold concentration can be decreased bySGLT2-inhibition. It has been shown in experiments with the SGLTinhibitor phlorizin that SGLT-inhibition will partially inhibit thereuptake of glucose from the glomerular filtrate into the blood leadingto a decrease in blood glucose concentration and to glucosuria.

Empagliflozin is a novel SGLT2 inhibitor that is described for thetreatment or improvement in glycemic control in patients with type 2diabetes mellitus, for example in WO 05/092877, WO 06/117359, WO06/120208, WO 2010/092126, WO 2010/092123, WO 2011/039107, WO2011/039108.

Accordingly, in a particular embodiment, a SGLT-2 inhibitor within themeaning of this invention is empagliflozin.

Further, the present invention relates to therapeutic (treatment orprevention) methods as described herein, in particular methods for theprevention or treatment of renal diseases, said method comprisingadministering an effective amount of a SGLT-2 inhibitor as describedherein and, optionally, one or more other active or therapeutic agentsas described herein to the patient in need thereof.

Chronic kidney disease (CKD), also known as chronic renal disease, is aprogressive loss in renal function over a period of months or years.Patients with renal disease, renal dysfunction or renal impairment mayinclude patients with chronic renal insufficiency or impairment, whichcan be stratified (if not otherwise noted) according to glomerularfiltration rate (GFR, ml/min/1.73 m²) into 5 disease stages: stage 1characterized by normal GFR 90 plus either persistent albuminuria (e.g.UACR ≧30 mg/g) or known structural or hereditary renal disease; stage 2characterized by mild reduction of GFR (GFR 60-89) describing mild renalimpairment; stage 3 characterized by moderate reduction of GFR (GFR30-59) describing moderate renal impairment; stage 4 characterized bysevere reduction of GFR (GFR 15-29) describing severe renal impairment;and terminal stage 5 characterized by requiring dialysis or GFR <15describing established kidney failure (end-stage renal disease, ESRD).

Chronic kidney disease and its stages (CKD 1-5) can be usuallycharacterized or classified accordingly, such as based on the presenceof either kidney damage (albuminuria) or impaired estimated glomerularfiltration rate (GFR <60 [ml/min/1.73 m²], with or without kidneydamage).

For the purpose of the present invention, the estimated glomerularfiltration rate (eGFR) is derived from the serum creatinine (SCr) valuebased on the MDRD formula below:

eGFR (mL/min/1.73m2)=175×[SCr (μmol/L)/88.4]−1.154×[age]−0.203×[0.742 ifpatient is female]×[1.212 if patient is of African origin]

For additional analyses, renal function can also be classified by theestimated creatinine clearance rate (eCCr) value, based on theCockcroft-Gault formula below:

eCCr (mL/min)=(140−age)×(weight in kg)×[0.85 if patient isfemale]/(72×SCr (mg/dL))

Renal function classification based on eCCr is similar to the eGFRclassification: normal renal function (≧90 mL/min), mild impairment (60to <90 mL/min), moderate impairment (30 to <60 mL/min), and severeimpairment (≧15 to <30 mL/min).

Generally, mild renal impairment according to the present inventioncorresponds to stage 2 chronic kidney disease, moderate renal impairmentaccording to the present invention generally corresponds to stage 3chronic kidney disease, and severe renal impairment according to thepresent invention generally corresponds to stage 4 chronic kidneydisease. Likewise, moderate A renal impairment according to the presentinvention generally corresponds to stage 3A chronic kidney disease andmoderate B renal impairment according to the present invention generallycorresponds to stage 3B chronic kidney disease.

Accordingly, in one aspect, the present invention relates to certainSGLT-2 inhibitors, for example empagliflozin, for use in treating,preventing, protecting against or delaying the progression of chronickidney disease in a patient, in particular a patient according to thepresent invention, for example the progression from stage 1 chronickidney disease to stage 2 chronic kidney disease, for example theprogression from stage 2 chronic kidney disease to stage 3 chronickidney disease, for example the progression from stage 3 chronic kidneydisease to stage 4 chronic kidney disease, for example the progressionfrom stage 4 chronic kidney disease to stage 5 chronic kidney disease.

In a further aspect of the present invention, the progression of chronickidney disease in a patient is for example the progression from stage 2chronic kidney disease to stage 3A chronic kidney disease, for examplethe progression from stage 3A chronic kidney disease to stage 3B chronickidney disease, for example the progression from stage 3B chronic kidneydisease to stage 4 chronic kidney disease.

In a further aspect of the present invention, the progression of chronickidney disease in a patient is for example the progression from stage 2chronic kidney disease to stage 4 or 5 chronic kidney disease, forexample the progression from stage 3 chronic kidney disease to stage 5chronic kidney disease, for example the progression from stage 3A or 3Bchronic kidney disease to stage 5 chronic kidney disease.

In a further aspect, a patient with chronic kidney disease according tothe present invention is a patient with stage 1 chronic kidney disease,stage 2 chronic kidney disease, stage 3 chronic kidney disease, stage 4chronic kidney disease, or stage 5 chronic kidney disease. In a furtheraspect, a patient with chronic kidney disease according to the presentinvention is a patient with stage 3A chronic kidney disease or stage 3Bchronic kidney disease,

In some aspects, renal disease, renal dysfunction, or insufficiency orimpairment of renal function (including mild, moderate and/or severerenal impairment) may also be suggested (if not otherwise noted) byelevated serum creatinine levels (e.g. serum creatinine levels above theupper limit of normal for their age, e.g. ≧130-150 μmol/l, or ≧1.5 mg/dl(≧136 μmol/l) in men and ≧1.4 mg/dl (≧124 μmol/l) in women) or abnormalcreatinine clearance (e.g. glomerular filtration rate (GFR) ≦30-60ml/min).

In some further aspects, mild renal impairment may be also suggested (ifnot otherwise noted) by a creatinine clearance of 50-80 ml/min(approximately corresponding to serum creatine levels of 1.7 mg/dL inmen and 1.5 mg/dL in women); moderate renal impairment may be e.g.suggested (if not otherwise noted) by a creatinine clearance of 30-50ml/min (approximately corresponding to serum creatinine levels of >1.7to ≦3.0 mg/dL in men and >1.5 to ≦2.5 mg/dL in women); and severe renalimpairment may be e.g. suggested (if not otherwise noted) by acreatinine clearance of <30 ml/min (approximately corresponding to serumcreatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women).Patients with end-stage renal disease require dialysis (e.g.hemodialysis or peritoneal dialysis).

In some further aspects, albuminuria can also be a sign of kidneydisease. Albuminuria stages may be classified as disclosed herein, andpatients may be stratified in category A1, which reflects noalbuminuria, category A2, which reflects microalbuminuria, and categoryA3, which reflects macroalbuminuria.

Accordingly, in a further aspect, a patient with chronic kidney diseaseaccording to the present invention is a patient with microalbuminuria orwith macroalbuminuria.

In one aspect of the present invention, it has been found thatempagliflozin has nephroprotective properties, in particular asdescribed herein. In particular, it has been shown that administrationof empagliflozin has the property to maintain or improve renal functionover time in certain patient group, for example as described herein, asdemonstrated after discontinuation of administration of empagliflozin.

In one aspect, a patient in the context of the present invention is apatient at risk of renal disease. A patient at risk of renal disease isfor example a patient with at least one of the following:

-   -   prediabetes, type 1 or 2 diabetes mellitus,    -   hypertension,    -   metabolic syndrome,    -   cardiovascular disease.

In one aspect, a patient in the context of the present invention is apatient with prediabetes, type 1 or 2 diabetes mellitus.

Type 2 diabetes mellitus is a common chronic and progressive diseasearising from a complex pathophysiology involving the dual endocrineeffects of insulin resistance and impaired insulin secretion with theconsequence not meeting the required demands to maintain plasma glucoselevels in the normal range. This leads to hyperglycaemia and itsassociated micro- and macrovascular complications or chronic damages,such as e.g. diabetic nephropathy, retinopathy or neuropathy, ormacrovascular (e.g. cardiovascular) complications. The vascular diseasecomponent plays a significant role, but is not the only factor in thespectrum of diabetes associated disorders. The high frequency ofcomplications leads to a significant reduction of life expectancy.Diabetes is currently the most frequent cause of adult-onset loss ofvision, renal failure, and amputation in the Industrialised Worldbecause of diabetes induced complications and is associated with a twoto five fold increase in cardiovascular disease risk. Type 1 diabetesmellitus (Type 1 diabetes), also called insulin dependent diabetesmellitus or juvenile diabetes, is a form of diabetes mellitus thatresults from autoimmune destruction of insulin-producing beta cells ofthe pancreas. The subsequent lack of insulin leads to increased bloodglucose concentrations and increased urinary glucose excretion. Theclassical symptoms are polyuria, polydipsia, polyphagia, and weightloss. Type 1 diabetes may be fatal unless treated with insulin.Complications from type 1 diabetes are the same or similar tocomplications from type 2 diabetes.

Large randomized studies have established that intensive and tightglycemic control during early (newly diagnoses to 5 years) stagediabetes has enduring beneficial effects and reduces the risk ofdiabetic complications, both micro- and macrovascular. However, manypatients with diabetes still develop diabetic complications despitereceiving intensified glycemic control.

Standard therapy of type 1 diabetes is insulin treatment. Therapies fortype 1 diabetes are for example described in WO 2012/062698.

The treatment of type 2 diabetes typically begins with diet andexercise, followed by oral antidiabetic monotherapy, and althoughconventional monotherapy may initially control blood glucose in somepatients, it is however associated with a high secondary failure rate.The limitations of single-agent therapy for maintaining glycemic controlmay be overcome, at least in some patients, and for a limited period oftime by combining multiple drugs to achieve reductions in blood glucosethat cannot be sustained during long-term therapy with single agents.Available data support the conclusion that in most patients with type 2diabetes current monotherapy will fail and treatment with multiple drugswill be required.

But, because type 2 diabetes is a progressive disease, even patientswith good initial responses to conventional combination therapy willeventually require an increase of the dosage or further treatment withinsulin because the blood glucose level is very difficult to maintainstable for a long period of time. Although existing combination therapyhas the potential to enhance glycemic control, it is not withoutlimitations (especially with regard to long term efficacy). Further,traditional therapies may show an increased risk for side effects, suchas hypoglycemia or weight gain, which may compromise their efficacy andacceptability.

Oral antidiabetic drugs conventionally used in therapy (such as e.g.first- or second-line, and/or mono- or (initial or add-on) combinationtherapy) include, without being restricted thereto, metformin,sulphonylureas, thiazolidinediones, DPP-4 inhibitors, glinides andα-glucosidase inhibitors.

Non-oral (typically injected) antidiabetic drugs conventionally used intherapy (such as e.g. first- or second-line, and/or mono- or (initial oradd-on) combination therapy) include, without being restricted thereto,GLP-1 or GLP-1 analogues, and insulin or insulin analogues.

The SGLT2 inhibitor therein also exhibits a very good efficacy withregard to glycemic control, in particular in view of a reduction offasting plasma glucose, postprandial plasma glucose and/or glycosylatedhemoglobin (HbA1c). By administering a pharmaceutical compositionaccording to this invention, a reduction of HbA1c equal to or greaterthan preferably 0.5%, even more preferably equal to or greater than 1.0%can be achieved and the reduction is particularly in the range from 1.0%to 2.0%.

In a further embodiment, a patient according to the present invention isa patient who shows one, two or more of the following conditions:

-   (a) a fasting blood glucose or serum glucose concentration greater    than 100 mg/dL, in particular greater than 125 mg/dL;-   (b) a postprandial plasma glucose equal to or greater than 140    mg/dL;-   (c) an HbA1c value equal to or greater than 6.5%, in particular    equal to or greater than 7.0%, especially equal to or greater than    7.5%, even more particularly equal to or greater than 8.0%.

In a further embodiment, a patient according to the present invention isa patient who shows one, two or more of the following conditions:

-   (a) insufficient glycemic control with diet and exercise alone;-   (b) insufficient glycemic control despite oral monotherapy with    metformin, in particular despite oral monotherapy at a maximal    tolerated dose of metformin;-   (c) insufficient glycemic control despite oral monotherapy with one    or more other antidiabetic agent, in particular despite oral    monotherapy at a maximal tolerated dose of the other antidiabetic    agent.

In a further embodiment, a patient according to the present invention isa patient who shows one, two or more of the following conditions:

-   (a) obesity (including class I, II and/or III obesity), visceral    obesity and/or abdominal obesity,-   (b) triglyceride blood level ≧150 mg/dL,-   (c) HDL-cholesterol blood level <40 mg/dL in female patients and <50    mg/dL in male patients,-   (d) a systolic blood pressure ≧130 mm Hg and a diastolic blood    pressure ≧85 mm Hg,-   (e) a systolic blood pressure ≧130 mm Hg and a diastolic blood    pressure ≧80 mm Hg,-   (f) a fasting blood glucose level ≧100 mg/dL.

In one embodiment, a patient according to the present invention is apatient with prediabetes, type 1 or 2 diabetes mellitus andhypertension. In one embodiment, a patient according to the presentinvention is a patient with prediabetes, type 1 or 2 diabetes mellitusand a systolic blood pressure ≧130 mm Hg and a diastolic blood pressure≧80 mm Hg.

In one embodiment, diabetes patients within the meaning of thisinvention may include patients who have not previously been treated withan antidiabetic drug (drug-naïve patients). Thus, in an embodiment, thetherapies described herein may be used in naïve patients. In anotherembodiment, diabetes patients within the meaning of this invention mayinclude patients with advanced or late stage type 2 diabetes mellitus(including patients with failure to conventional antidiabetic therapy),such as e.g. patients with inadequate glycemic control on one, two ormore conventional oral and/or non-oral antidiabetic drugs as definedherein, such as e.g. patients with insufficient glycemic control despite(mono-)therapy with metformin, a thiazolidinedione (particularlypioglitazone), a sulphonylurea, a glinide, a DPP-4 inhibitor, GLP-1 orGLP-1 analogue, insulin or insulin analogue, or an α-glucosidaseinhibitor, or despite dual combination therapy withmetformin/sulphonylurea, metformin/thiazolidinedione (particularlypioglitazone), metformin/DPP-4 inhibitor, sulphonylurea/α-glucosidaseinhibitor, pioglitazone/sulphonylurea, metformin/insulin,pioglitazone/insulin or sulphonylurea/insulin.

In one embodiment, a patient according to the present invention is apatient receiving treatment with a non-oral antidiabetic drug, forexample GLP1-analog (for example short acting GLP-1 analog such asexenatide, liraglutide or lixisenatide, or long-acting GLP-1 analog suchas exenatide extended-release, albiglutide or dulaglutide), for exampleinsulin or insulin analogue, for example basal insulin, such asglargine, detemir and/or NPH insulin.

In one embodiment, a patient according to the present invention is apatient receiving treatment with insulin or insulin analogue. An insulinor insulin analogue may include normal insulin, human insulin, insulinderivatives, zinc insulins and insulin analogues, including formulationsthereof with modified release profiles, in particular as used in thetherapy of humans. The insulin may be selected from the group consistingof:

-   -   rapid-acting insulins,    -   short-acting insulins,    -   intermediate-acting insulins,    -   long-acting insulins,        and mixtures thereof.

Mixtures of insulins may comprise mixtures of short- or rapid-actinginsulins with long-acting insulins. For example such mixtures aremarketed as Actraphane/Mixtard or Novomix.

The term “insulin” in the scope of the present invention covers insulinsas described hereinbefore and hereinafter which are administered to thepatient via injection, preferably subcutaneous injection, via infusion,including pumps, via inhalation or other routes of administration.Insulins to be administered via inhalation are for example Exubera(Pfizer), AIR (Lilly) and AER (Novo Nordisk).

Rapid-acting insulins usually start lowering the blood glucose withinabout 5 to 15 minutes and are effective for about 3 to 4 hours. Examplesof rapid-acting insulins are insulin aspart, insulin lispro and insulinglulisine. Insulin Lispro is marketed under the trade name Humalog andLiprolog. Insulin Aspart is marketed under the trade names NovoLog andNovoRapid. Insulin glulisine is marketed under the trade name Apidra.

Short-acting insulins usually start lowering the blood glucose withinabout 30 minutes and are effective about 5 to 8 hours. An example isregular insulin or human insulin.

Intermediate-acting insulins usually start lowering the blood glucosewithin about 1 to 3 hours and are effective for about 16 to 24 hours. Anexample is NPH insulin, also known as Humulin N, Novolin N, Novolin NPHand isophane insulin. Another example are lente insulins, such asSemilente or Monotard.

Long-acting insulins usually start lowering the blood glucose within 1to 6 hours and are effective for up to about 24 hours or even up to orbeyond 32 hours. Long-acting insulin usually provides a continuous levelof insulin activity (for up to 24-36 hours) and usually operates at amaximum strength (with flat action profile) after about 8-12 hours,sometimes longer. Long-acting insulin is usually administered in themorning or before bed. Examples of long-acting insulin may include, butare not limited to, insulin glargine, insulin detemir or insulindegludec, which are insulin analogues, and ultralente insulin, which isregular human insulin formulated for slow absorption. Long-actinginsulin is suited to provide for basal, as opposed to prandial, insulinrequirements (e.g. to control hyperglycemia). Long-acting insulin may betypically administered ranging from twice or once daily, over thriceweekly up to once weekly (ultra long-acting insulin). Insulin glargineis marketed under the trade name Lantus for example. Insulin detemir ismarketed under the tradename Levemir for example.

In one embodiment, a long-acting insulin is an acylated derivative ofhuman insulin. Acylated insulin derivatives may be such wherein alipophilic group is attached to the lysine residue in position B29. Acommercial product is Levemir® comprising Lys^(B29)(N^(t)-tetradecanoyl)des(B30) human insulin (insulin detemir). Another example isN^(tB29)-(N^(α)-(ω-carboxypentadecanoyl)-L-γ-glutamyl) des(B30) humaninsulin (insulin degludec).

In one embodiment, a long-acting insulin is such comprising positivelycharged amino acids such as Arg attached to the C-terminal end of theB-chain. A commercial product is Lantus® (insulin glargine) comprisingGly^(A21), Arg^(B31), Arg^(B32) human insulin.

In one embodiment, a patient according to the present invention is apatient receiving treatment with a mixture of insulin and GLP-1 analog,for example a mixture of insulin glargine and lixisenatide.

In a further aspect, a patient according to the present invention is apatient with or at risk of a cardiovascular disease.

In one embodiment, the patient is a patient with one or morecardiovascular risk factors selected from A), B), C) and D), for examplea patient with type 1 or type 2 diabetes mellitus or with pre-diabeteswith one or more cardiovascular risk factors selected from A), B), C)and D):

A) previous or existing vascular disease selected from myocardialinfarction, coronary artery disease, percutaneous coronary intervention,coronary artery by-pass grafting, ischemic or hemorrhagic stroke,congestive heart failure, and peripheral occlusive arterial disease,B) advanced age >/=60-70 years, andC) one or more cardiovascular risk factors selected from

-   -   advanced type 2 diabetes mellitus >10 years duration,    -   hypertension,    -   current daily cigarette smoking,    -   dyslipidemia,    -   obesity,    -   age >/=40,    -   metabolic syndrome, hyperinsulinemia or insulin resistance, and    -   hyperuricemia, erectile dysfunction, polycystic ovary syndrome,        sleep apnea, or family history of vascular disease or        cardiomyopathy in first-degree relative;        D) one or more of the following:    -   confirmed history of myocardial infarction,    -   unstable angina with documented multivessel coronary disease or        positive stress test,    -   multivessel Percutaneous Coronary Intervention,    -   multivessel Coronary Artery By-pass Grafting (CABG),    -   history of ischemic or hemorrhagic stroke,    -   peripheral occlusive arterial disease.

In a further aspect of the present invention, a patient havingcardiovascular disease is defined as having at least one of thefollowing:

-   -   Confirmed history of myocardial infarction; or    -   Evidence of multivessel coronary artery disease, in 2 or more        major coronary arteries, irrespective of the revascularization        status, i.e.        -   a) Either the presence of a significant stenosis (imaging            evidence of at least 50% narrowing of the luminal diameter            measured during a coronary angiography or a multi-sliced            computed tomography angiography), in 2 or more major            coronary arteries,        -   b) Or a previous revascularisation (percutaneous            transluminal coronary angioplasty with or without stent, or            coronary artery bypass grafting), in 2 or more major            coronary arteries,        -   c) Or the combination of previous revascularisation in one            major coronary artery (percutaneous transluminal coronary            angioplasty with or without stent, or coronary artery bypass            grafting), and the presence of a significant stenosis in            another major coronary artery (imaging evidence of at least            50% narrowing of the luminal diameter measured during a            coronary angiography or a multi-sliced computed tomography            angiography),            -   Note: A disease affecting the left main coronary artery                is considered as a 2-vessel disease.    -   Evidence of a single vessel coronary artery disease with:        -   a) The presence of a significant stenosis i.e. the imaging            evidence of at least 50% narrowing of the luminal diameter            of one major coronary artery in patients not subsequently            successfully revascularised (measured during a coronary            angiography or a multi-sliced computed tomography            angiography)        -   b) And at least one of the following (either (i) or (ii)):            -   i. A positive non invasive stress test, confirmed by                either:                -   1. A positive exercise tolerance test in patients                    without a complete left bundle branch block,                    Wolff-Parkinson-White syndrome, or paced ventricular                    rhythm, or                -   2. A positive stress echocardiography showing                    regional systolic wall motion abnormalities, or                -   3. A positive scintigraphic test showing                    stress-induced ischemia, i.e. the development of                    transient perfusion defects during myocardial                    perfusion imaging;            -   ii. Or patient discharged from hospital with a                documented diagnosis of unstable angina within 12 months                prior to selection.    -   Episode of unstable angina with confirmed evidence of coronary        multivessel or single vessel disease as defined above.    -   History of ischemic or haemorrhagic stroke    -   Presence of peripheral artery disease (symptomatic or not)        documented by either: previous limb angioplasty, stenting or        bypass surgery; or previous limb or foot amputation due to        circulatory insufficiency; or angiographic evidence of        significant (>50%) peripheral artery stenosis in at least one        limb; or evidence from a non-invasive measurement of significant        (>50% or as reported as hemodynamically significant) peripheral        artery stenosis in at least one limb; or ankle brachial index of        <0.9 in at least one limb.

In a further aspect of the present invention, a patient havingcardiovascular disease is defined as having at least one of thefollowing:

-   -   a) Confirmed history of myocardial infarction,    -   b) Unstable angina with documented multivessel coronary disease        (at least two major coronary arteries in angiogram) or positive        stress test (ST segment depression >=2 mm or a positive nuclear        perfusion scintigram),    -   c) Multivessel Percutaneous Coronary Intervention (PCI),    -   d) Multivessel Coronary Artery By-pass Grafting (CABG),        including with recurrent angina following surgery,    -   e) History of ischemic or hemorrhagic stroke,    -   f) Peripheral occlusive arterial disease (previous limb bypass        surgery or percutaneous transluminal angioplasty; previous limb        or foot amputation due to circulatory insufficiency,        angiographic or imaging detected (for example: ultrasound,        Magnetic Resonance Imaging) significant vessel stenosis of major        limb arteries).

Accordingly, in one aspect, the present invention relates to a certainSGLT-2 inhibitor, in particular empagliflozin, for use in a method asdescribed herein, in a patient with one or more risk factors selectedfrom A), B), C) and D):

A) previous or existing vascular disease (such as e.g. myocardialinfarction (e.g. silent or non-silent), coronary artery disease,percutaneous coronary intervention, coronary artery by-pass grafting,ischemic or hemorrhagic stroke, congestive heart failure (e.g. NYHAclass I, II, III or IV, e.g. left ventricular function <40%), orperipheral occlusive arterial disease),B) advanced age (such as e.g. age >/=60-70 years), andC) one or more cardiovascular risk factors selected from

-   -   advanced type 1 or type 2 diabetes mellitus (such as e.g. >10        years duration),    -   hypertension (such as e.g. >130/80 mm Hg, or systolic blood        pressure >140 mmHg or on at least one blood pressure lowering        treatment),    -   current daily cigarette smoking,    -   dyslipidemia (such as e.g. atherogenic dyslipidemia,        postprandial lipemia, or high level of LDL cholersterol (e.g.        LDL cholesterol >/=130-135 mg/dL), low level of HDL cholesterol        (e.g. <35-40 mg/dL in men or <45-50 mg/dL in women) and/or high        level of triglycerides (e.g. >200-400 mg/dL) in the blood, or on        at least one treatment for lipid abnormality),    -   obesity (such as e.g. abdominal and/or visceral obesity, or body        mass index >/=45 kg/m2),    -   age >/=40,    -   metabolic syndrome, hyperinsulinemia or insulin resistance, and    -   hyperuricemia, erectile dysfunction, polycystic ovary syndrome,        sleep apnea, or family history of vascular disease or        cardiomyopathy in first-degree relative,        D) one or more of the following:    -   confirmed history of myocardial infarction,    -   unstable angina with documented multivessel coronary disease or        positive stress test,    -   multivessel Percutaneous Coronary Intervention,    -   multivessel Coronary Artery By-pass Grafting (CABG),    -   history of ischemic or hemorrhagic stroke,    -   peripheral occlusive arterial disease.        said method comprising administering a therapeutically effective        amount of the SGLT-2 inhibitor, optionally in combination with        one or more other therapeutic substances, to the patient.

In one aspect, a patient in the context of the present invention is apatient with hypertension. In one aspect, a patient in the context ofthe present invention is a patient with metabolic syndrome.

The present invention further relates to a pharmaceutical compositioncomprising a certain SGLT-2 inhibitor as defined herein, empagliflozin,for use in the therapies described herein, for example in a patient orpatient group as described herein.

When this invention refers to patients requiring treatment orprevention, it relates primarily to treatment and prevention in humans,but the pharmaceutical composition may also be used accordingly inveterinary medicine in mammals. In the scope of this invention adultpatients are preferably humans of the age of 18 years or older. Also inthe scope of this invention, patients are adolescent humans, i.e. humansof age 10 to 17 years, preferably of age 13 to 17 years.

In a further aspect, a method according to the present invention furthercomprises improving glycemic control in patients having type 1 or type 2diabetes mellitus or showing first signs of pre-diabetes.

In a further aspect, a method according to the present invention furthercomprises improving glycemic control and/or for reducing of fastingplasma glucose, of postprandial plasma glucose and/or of glycosylatedhemoglobin HbA1c in a patient in need thereof who is diagnosed withimpaired glucose tolerance (IGT), impaired fasting blood glucose (IFG)with insulin resistance, with metabolic syndrome and/or with type 2 ortype 1 diabetes mellitus.

In a further aspect, a method according to the present invention furthercomprises improving glycemic control in patients, in particular in adultpatients, with type 2 diabetes mellitus as an adjunct to diet andexercise.

Within the scope of the present invention it has now been found thatcertain SGLT-2 inhibitors as defined herein, optionally in combinationwith one or more other therapeutic substances (e.g. selected from thosedescribed herein), as well as pharmaceutical combinations, compositionsor combined uses according to this invention of such SGLT-2 inhibitorsas defined herein have properties, which make them suitable for thepurpose of this invention and/or for fulfilling one or more of aboveneeds. The present invention thus relates to a certain SGLT-2 inhibitoras defined herein, preferably empagliflozin, for use in the therapiesdescribed herein.

Furthermore, it can be found that the administration of a pharmaceuticalcomposition according to this invention results in no risk or in a lowrisk of hypoglycemia. Therefore, a treatment or prophylaxis according tothis invention is also advantageously possible in those patients showingor having an increased risk for hypoglycemia.

It will be appreciated that the amount of the pharmaceutical compositionaccording to this invention to be administered to the patient andrequired for use in treatment or prophylaxis according to the presentinvention will vary with the route of administration, the nature andseverity of the condition for which treatment or prophylaxis isrequired, the age, weight and condition of the patient, concomitantmedication and will be ultimately at the discretion of the attendantphysician. In general, however, the SGLT2 inhibitor according to thisinvention is included in the pharmaceutical composition or dosage formin an amount sufficient that by its administration the glycemic controlin the patient to be treated is improved.

In the following preferred ranges of the amount of the SGLT2 inhibitorto be employed in the pharmaceutical composition and the methods anduses according to this invention are described. These ranges refer tothe amounts to be administered per day with respect to an adult patient,in particular to a human being, for example of approximately 70 kg bodyweight, and can be adapted accordingly with regard to an administration2, 3, 4 or more times daily and with regard to other routes ofadministration and with regard to the age of the patient. Within thescope of the present invention, the pharmaceutical composition ispreferably administered orally. Other forms of administration arepossible and described hereinafter. Preferably the one or more dosageforms comprising the SGLT2 inhibitor is oral or usually well known.

In general, the amount of the SGLT2 inhibitor in the pharmaceuticalcomposition and methods according to this invention is preferably theamount usually recommended for a monotherapy using said SGLT2 inhibitor.

The preferred dosage range of the SGLT2 inhibitor is in the range from0.5 mg to 200 mg, even more preferably from 1 to 100 mg, most preferablyfrom 1 to 50 mg per day. In one aspect, a preferred dosage of the SGLT2inhibitor empagliflozin is 10 mg or 25 mg per day. The oraladministration is preferred. Therefore, a pharmaceutical composition maycomprise the hereinbefore mentioned amounts, in particular from 1 to 50mg or 1 to 25 mg. Particular dosage strengths (e.g. per tablet orcapsule) are for example 1, 2.5, 5, 7.5, 10, 12.5, 15, 20, 25 or 50 mgof the SGLT2 inhibitor, in particular empagliflozin. In one aspect, apharmaceutical composition comprises 10 mg or 25 mg of empagliflozin.The application of the active ingredient may occur up to three times aday, preferably one or two times a day, most preferably once a day.

A pharmaceutical composition which is present as a separate or multipledosage form, preferably as a kit of parts, is useful in combinationtherapy to flexibly suit the individual therapeutic needs of thepatient.

According to a first embodiment a preferred kit of parts comprises acontainment containing a dosage form comprising the SGLT2 inhibitor andat least one pharmaceutically acceptable carrier.

A further aspect of the present invention is a manufacture comprisingthe pharmaceutical composition being present as separate dosage formsaccording to the present invention and a label or package insertcomprising instructions that the separate dosage forms are to beadministered in combination or alternation.

According to a first embodiment a manufacture comprises (a) apharmaceutical composition comprising a SGLT2 inhibitor according to thepresent invention and (b) a label or package insert which comprisesinstructions that the medicament is to be administered.

The desired dose of the pharmaceutical composition according to thisinvention may conveniently be presented in a once daily or as divideddose administered at appropriate intervals, for example as two, three ormore doses per day.

The pharmaceutical composition may be formulated for oral, rectal,nasal, topical (including buccal and sublingual), transdermal, vaginalor parenteral (including intramuscular, subcutaneous and intravenous)administration in liquid or solid form or in a form suitable foradministration by inhalation or insufflation. Oral administration ispreferred. The formulations may, where appropriate, be convenientlypresented in discrete dosage units and may be prepared by any of themethods well known in the art of pharmacy. All methods include the stepof bringing into association the active ingredient with one or morepharmaceutically acceptable carriers, like liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired formulation.

The pharmaceutical composition may be formulated in the form of tablets,granules, fine granules, powders, capsules, caplets, soft capsules,pills, oral solutions, syrups, dry syrups, chewable tablets, troches,effervescent tablets, drops, suspension, fast dissolving tablets, oralfast-dispersing tablets, etc.

The pharmaceutical composition and the dosage forms preferably comprisesone or more pharmaceutical acceptable carriers which must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.Examples of pharmaceutically acceptable carriers are known to the oneskilled in the art.

Pharmaceutical compositions suitable for oral administration mayconveniently be presented as discrete units such as capsules, includingsoft gelatin capsules, cachets or tablets each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution, a suspension or as an emulsion, for example as syrups,elixirs or self-emulsifying delivery systems (SEDDS). The activeingredients may also be presented as a bolus, electuary or paste.Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, fillers, lubricants, disintegrants,or wetting agents. The tablets may be coated according to methods wellknown in the art. Oral liquid preparations may be in the form of, forexample, aqueous or oily suspensions, solutions, emulsions, syrups orelixirs, or may be presented as a dry product for constitution withwater or other suitable vehicle before use. Such liquid preparations maycontain conventional additives such as suspending agents, emulsifyingagents, non-aqueous vehicles (which may include edible oils), orpreservatives.

The pharmaceutical composition according to the invention may also beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredients may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Pharmaceutical compositions suitable for rectal administration whereinthe carrier is a solid are most preferably presented as unit dosesuppositories. Suitable carriers include cocoa butter and othermaterials commonly used in the art, and the suppositories may beconveniently formed by admixture of the active compound(s) with thesoftened or melted carrier(s) followed by chilling and shaping inmoulds.

The pharmaceutical compositions and methods according to this inventionshow advantageous effects in the treatment and prevention of thosediseases and conditions as described hereinbefore. Advantageous effectsmay be seen for example with respect to efficacy, dosage strength,dosage frequency, pharmacodynamic properties, pharmacokineticproperties, fewer adverse effects, convenience, compliance, etc.

Methods for the manufacture of SGLT2 inhibitors according to thisinvention and of prodrugs thereof are known to the one skilled in theart. Advantageously, the compounds according to this invention can beprepared using synthetic methods as described in the literature,including patent applications as cited hereinbefore. Preferred methodsof manufacture are described in the WO 2006/120208 and WO 2007/031548.With regard to empagliflozin an advantageous crystalline form isdescribed in the international patent application WO 2006/117359 whichhereby is incorporated herein in its entirety.

The active ingredients may be present in the form of a pharmaceuticallyacceptable salt. Pharmaceutically acceptable salts include, withoutbeing restricted thereto, such as salts of inorganic acid likehydrochloric acid, sulfuric acid and phosphoric acid; salts of organiccarboxylic acid like oxalic acid, acetic acid, citric acid, malic acid,benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acidand glutamic acid and salts of organic sulfonic acid likemethanesulfonic acid and p-toluenesulfonic acid. The salts can be formedby combining the compound and an acid in the appropriate amount andratio in a solvent and decomposer. They can be also obtained by thecation or anion exchange from the form of other salts.

The active ingredients or a pharmaceutically acceptable salt thereof maybe present in the form of a solvate such as a hydrate or alcohol adduct.

Pharmaceutical compositions or combinations for use in these therapiescomprising the SGLT-2 inhibitor as defined herein optionally togetherwith one or more other active substances are also contemplated.

Further, the present invention relates to the SGLT-2 inhibitors,optionally in combination with one, two or more further active agents,each as defined herein, for use in the therapies as described herein.

Further, the present invention relates to the use of the SGLT-2inhibitors, optionally in combination with one, two or more furtheractive agents, each as defined herein, for preparing pharmaceuticalcompositions which are suitable for the treatment and/or preventionpurposes of this invention.

The present invention further relates to a combination comprising acertain SGLT-2 inhibitor (particularly empagliflozin) and one or moreother active substances selected from other antidiabetic substances,particularly for simultaneous, separate or sequential use in thetherapies described herein.

The present invention further relates to a combination comprising acertain SGLT-2 inhibitor (particularly empagliflozin) and one or moreother antidiabetics selected from the group consisting of metformin, asulphonylurea, nateglinide, repaglinide, a thiazolidinedione, aPPAR-gamma-agonist, an alpha-glucosidase inhibitor, insulin or aninsulin analogue, GLP-1 or a GLP-1 analogue and a DPP-4 inhibitor,particularly for simultaneous, separate or sequential use in thetherapies described herein.

The present invention further relates to a method according to thepresent invention further comprising treating and/or preventingmetabolic disorders, especially type 2 diabetes mellitus and/orconditions related thereto (e.g. diabetic complications) comprising thecombined (e.g. simultaneous, separate or sequential) administration ofan effective amount of empagliflozin and one or more other antidiabeticsselected from the group consisting of metformin, a sulphonylurea,nateglinide, repaglinide, a PPAR-gamma-agonist, an alpha-glucosidaseinhibitor, insulin or an insulin analogue, GLP-1 or a GLP-1 analogue anda DPP-4 inhibitor, to the patient (particularly human patient) in needthereof, such as e.g. a patient as described herein.

The present invention further relates to therapies or therapeuticmethods described herein, further comprising treating and/or preventingmetabolic disorders, especially type 2 diabetes mellitus and/orconditions related thereto (e.g. diabetic complications), comprisingadministering a therapeutically effective amount of empagliflozin and,optionally, one or more other therapeutic agents, such as e.g.antidiabetics selected from the group consisting of metformin, asulphonylurea, nateglinide, repaglinide, a PPAR-gamma-agonist, analpha-glucosidase inhibitor, insulin or an insulin analogue, GLP-1 or aGLP-1 analogue and a DPP-4 inhibitor, to the patient (particularly humanpatient) in need thereof, such as e.g. a patient as described herein.

Unless otherwise noted, combination therapy may refer to first line,second line or third line therapy, or initial or add-on combinationtherapy or replacement therapy.

The present invention further relates to a certain SGLT-2 inhibitor asdefined herein, preferably empagliflozin, in combination with metformin,for use in the therapies described herein.

Metformin is usually given in doses varying from about 500 mg to 2000 mgup to 2500 mg per day using various dosing regimens from about 100 mg to500 mg or 200 mg to 850 mg (1-3 times a day), or about 300 mg to 1000 mgonce or twice a day, or delayed-release metformin in doses of about 100mg to 1000 mg or preferably 500 mg to 1000 mg once or twice a day orabout 500 mg to 2000 mg once a day. Particular dosage strengths may be250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride.

For children 10 to 16 years of age, the recommended starting dose ofmetformin is 500 mg given once daily. If this dose fails to produceadequate results, the dose may be increased to 500 mg twice daily.Further increases may be made in increments of 500 mg weekly to amaximum daily dose of 2000 mg, given in divided doses (e.g. 2 or 3divided doses). Metformin may be administered with food to decreasenausea.

An example of a DPP-4 inhibitor is linagliptin, which is usually givenin a dosage of 5 mg per day.

A dosage of pioglitazone is usually of about 1-10 mg, 15 mg, 30 mg, or45 mg once a day. Rosiglitazone is usually given in doses from 4 to 8 mgonce (or divided twice) a day (typical dosage strengths are 2, 4 and 8mg).

Glibenclamide (glyburide) is usually given in doses from 2.5-5 to 20 mgonce (or divided twice) a day (typical dosage strengths are 1.25, 2.5and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mgonce (or divided twice) a day (typical dosage strengths are 1.5, 3, 4.5and 6 mg).

Glipizide is usually given in doses from 2.5 to 10-20 mg once (or up to40 mg divided twice) a day (typical dosage strengths are 5 and 10 mg),or extended-release glibenclamide in doses from 5 to 10 mg (up to 20 mg)once a day (typical dosage strengths are 2.5, 5 and 10 mg).

Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) oncea day (typical dosage strengths are 1, 2 and 4 mg).

The non-sulphonylurea insulin secretagogue nateglinide is usually givenin doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosagestrengths are 60 and 120 mg); repaglinide is usually given in doses from0.5 to 4 mg with meals (up to 16 mg/day, typical dosage strengths are0.5, 1 and 2 mg). A dual combination of repaglinide/metformin isavailable in dosage strengths of 1/500 and 2/850 mg.

In one aspect of the present invention, the one or more othertherapeutic substances are RAAS inhibitors(Renin-Angiotensin-Aldosterone System). In one aspect of the presentinvention, the one or more other therapeutic substances is a directrenin inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/oran angiotensin II receptor blocker (ARB).

In one aspect, a SGLT-2 inhibitor, in particular empagliflozin is usedin a method according to the present invention in addition to a RAASinhibitor, in particular a direct renin inhibitor, anAngiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB).

In another embodiment of the present invention, certain SGLT-2inhibitors, in particular empagliflozin, are useful in the therapy of apatient with chronic kidney disease and albuminuria despite therapy witha direct renin inhibitor, an angiotensin-converting enzyme (ACE)inhibitor and/or an angiotensin II receptor blocker (ARB), in particulara patient described herein.

In another embodiment of the present invention, certain a SGLT-2inhibitors, in particular empagliflozin, are useful in a methodaccording to the present invention on top of direct renin inhibitortherapy, angiotensin-converting enzyme (ACE) inhibitor therapy and/orangiotensin II receptor blockade (ARB) therapy.

Accordingly, in a further embodiment, the present invention relates to acertain SGLT-2 inhibitor, in particular empagliflozin, in combinationwith a RAAS inhibitor, for example a direct renin inhibitor, anAngiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB), for use in the therapy as described herein, forexample in a patient as described herein.

In one aspect, the present invention relates to certain SGLT-2inhibitors, for example empagliflozin, in combination with a RAASinhibitor, for example a direct renin inhibitor, anAngiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB), for use in treating, preventing, protectingagainst, reducing the risk of, delaying the occurrence of and/ordelaying the progression of chronic kidney disease in patients, forexample patients with prediabetes, type 1 or type 2 diabetes mellitus.

In a further aspect, the present invention relates to certain SGLT-2inhibitors, for example empagliflozin, in combination with a RAASinhibitor, for example a direct renin inhibitor, anAngiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB), for use in treating, preventing, protectingagainst or delaying new onset of albuminuria in patients.

In a further aspect, the present invention relates to certain SGLT-2inhibitors, for example empagliflozin, in combination with a RAASinhibitor, for example a direct renin inhibitor, anAngiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker

(ARB), for use in treating, preventing, protecting against or delayingthe progression from no albuminuria to micro- or macroalbuminuria in apatient at risk for renal disease.

In a further aspect, the present invention relates to certain SGLT-2inhibitors, for example empagliflozin, in combination with a RAASinhibitor, for example a direct renin inhibitor, anAngiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB), for use in treating, preventing, protectingagainst or delaying the progression from microalbuminuria tomacroalbuminuria in a patient with chronic kidney disease.

In a further aspect, the present invention relates to certain SGLT-2inhibitors, for example empagliflozin, in combination with a RAASinhibitor, for example a direct renin inhibitor, anAngiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB), for use in treating, preventing, protectingagainst delaying the progression of chronic kidney disease in a patientwith chronic kidney disease.

In a further aspect, the present invention relates to certain SGLT-2inhibitors, for example empagliflozin, in combination with a RAASinhibitor, for example a direct renin inhibitor, anAngiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB), for use in treating, preventing, protectingagainst or delaying the occurrence of:

-   -   new onset of albuminuria,    -   doubling of serum creatinine level accompanied by an eGFR (based        on modification of diet in renal disease (MDRD) formula)        mL/min/1.73 m2,    -   need for continuous renal replacement therapy, or    -   death due to renal disease.

In one aspect, a patient according of the present invention is a patientwith prediabetes, type 1 or type 2 diabetes mellitus. In one aspect, apatient according to the present invention is a patient is a patient atrisk for renal disease. In one aspect, a patient according to thepresent invention is a patient with or at risk of a cardiovasculardisease. In one aspect, a patient according to the present invention isa patient with prediabetes, type 1 or type 2 diabetes mellitus and withor at risk of a cardiovascular disease.

Examples of Angiotensin-Converting Enzyme (ACE) inhibitors areBenazepril, Captopril, ramipril, lisinopril, Moexipril, cilazapril,quinapril, captopril, enalapril, benazepril, perindopril, fosinopril andtrandolapril; the dosage(s) of some of these medications are for exampleshown below:

-   -   Benazepril (Lotensin), 5 mg, 10 mg, 20 mg, and 40 mg for oral        administration    -   Captopril (Capoten), 12.5 mg, 25 mg, 50 mg, and 100 mg as scored        tablets for oral administration    -   Enalapril (Vasotec), 2.5 mg, 5 mg, 10 mg, and 20 mg tablets for        oral administration    -   Fosinopril (Monopril), for oral administration as 10 mg, 20 mg,        and 40 mg tablets    -   Lisinopril (Prinivil, Zestril), 5 mg, 10 mg, and 20 mg tablets        for oral administration    -   Moexipril (Univasc), 7.5 mg and 15 mg for oral administration    -   Perindopril (Aceon), 2 mg, 4 mg and 8 mg strengths for oral        administration    -   Quinapril (Accupril), 5 mg, 10 mg, 20 mg, or 40 mg of quinapril        for oral administration    -   Ramipril (Altace), 1.25 mg, 2.5 mg, 5, mg, 10 mg    -   Trandolapril (Mavik), 1 mg, 2 mg, or 4 mg of trandolapril for        oral administration

Examples of angiotensin II receptor blockers (ARBs) are telmisartan,candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan andeprosartan; the dosage(s) of some of these medications are for exampleshown below:

-   -   Candesartan (Atacand), 4 mg, 8 mg, 16 mg, or 32 mg of        candesartan cilexetil    -   Eprosartan (Teveten), 400 mg or 600 mg    -   Irbesartan (Avapro), 75 mg, 150 mg, or 300 mg of irbesartan.    -   Losartan (Cozaar), 25 mg, 50 mg or 100 mg of losartan potassium    -   Telmisartan (Micardis), 40 mg/12.5 mg, 80 mg/12.5 mg, and 80        mg/25 mg telmisartan and hydrochlorothiazide    -   Valsartan (Diovan), 40 mg, 80 mg, 160 mg or 320 mg of valsartan

A dosage of telmisartan is usually from 20 mg to 320 mg or 40 mg to 160mg per day.

An example of a direct renin inhibitor is aliskiren (Tekturna). A dosageof aliskiren may be 150 mg or 300 mg per day.

Within this invention it is to be understood that the combinations,compositions or combined uses according to this invention may envisagethe simultaneous, sequential or separate administration of the activecomponents or ingredients.

In this context, “combination” or “combined” within the meaning of thisinvention may include, without being limited, fixed and non-fixed (e.g.free) forms (including kits) and uses, such as e.g. the simultaneous,sequential or separate use of the components or ingredients.

The combined administration of this invention may take place byadministering the active components or ingredients together, such ase.g. by administering them simultaneously in one single or in twoseparate formulations or dosage forms. Alternatively, the administrationmay take place by administering the active components or ingredientssequentially, such as e.g. successively in two separate formulations ordosage forms.

For the combination therapy of this invention the active components oringredients may be administered separately (which implies that they areformulated separately) or formulated altogether (which implies that theyare formulated in the same preparation or in the same dosage form).Hence, the administration of one element of the combination of thepresent invention may be prior to, concurrent to, or subsequent to theadministration of the other element of the combination.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a SGLT-2 inhibitor, for example empagliflozin, incombination with a RAAS inhibitor, for example a direct renin inhibitor,an Angiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensinII receptor blocker (ARB), for example as described herein.

Further embodiments, features and advantages of the present inventionmay become apparent from the following examples. The following examplesserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

EXAMPLES Example 1 Empagliflozin in Patients with Type 2 DiabetesMellitus (T2DM) and Renal Impairment (RI)

A Phase III trial investigated the efficacy and safety of empagliflozin(EMPA) as add-on to existing therapy for 52 weeks in patients with T2DMand RI. Patients with mild RI (eGFR [MDRD equation] ≧60 to <90mL/min/1.73 m²) received EMPA 10 or 25 mg qd or placebo (PBO). Patientswith moderate RI (eGFR 30 to <60 mL/min/1.73 m²) received EMPA 25 mg qdor PBO. Patients with severe RI (eGFR 5 to <30 mL/min/1.73 m²) receivedEMPA 25 mg qd or PBO.

In patients with type 2 diabetes and mild renal impairment, treatmentwith empagliflozin 10 and 25 mg at week 52 resulted in a small decreasein eGFR. However, mean eGFR increased to a value slightly above baselineat the 3-week follow up visit in the empagliflozin treatment groups; incontrast, in the placebo group, mean eGFR further decreased (Table 1A).

TABLE 1A Descriptive statistics for eGFR over time in patients with mildrenal impairment Empa Empa Placebo 10 mg 25 mg Number of patients 32(100.0) 41 (100.0) 38 (100.0) N (%) Baseline eGFR N* (%) 32 (100.0) 41(100.0) 38 (100.0) Mean (SD) 72.24 (12.68) 68.42 (8.23) 72.01 (10.84)[mL/min/1.73 m²] End-of treatment eGFR N* (%) 32 (100.0) 38 (92.7) 37(97.4) Mean (SD) 70.34 (11.42) 68.07 (11.36) 66.25 (13.00) [mL/min/1.73m²] Mean change from −1.89 (11.14) −0.76 (9.42) −5.67 (10.37) baseline(SD) [mL/min/1.73 m²] Follow-up eGFR N* (%) 30 (93.8) 38 (92.7) 37(97.4) Mean (SD) 68.20 (11.16) 69.84 (11.29) 73.38 (13.67) [mL/min/1.73m²] Mean change from −3.84 (11.63) 2.06 (8.91) 1.28 (8.89) baseline (SD)[mL/min/1.73 m²]

In patients with type 2 diabetes and moderate renal impairment,treatment with empagliflozin 25 mg at week 52 resulted a small decreasein eGFR while no change was seen for the placebo group. However, at the3-week follow-up visit mean eGFR increased to a value slightly abovebaseline in the empagliflozin treatment group (Table 1B). Similarresults were seen in patients with CKD 3A and B.

TABLE 1B Descriptive statistics for eGFR over time in patients withmoderate renal impairment Empa Placebo 25 mg Number of patients N (%)104 (100.0) 105 (100.0) Baseline eGFR N* (%) 104 (100.0) 105 (100.0)Mean (SD) [mL/min/1.73 m²] 43.35 (10.39) 43.84 (8.70) End-of treatmenteGFR N* (%) 102 (98.1) 101 (96.2) Mean (SD) [mL/min/1.73 m²] 43.70(11.08) 40.58 (10.26) Mean change from baseline (SD) 0.04 (7.16) −3.55(6.63) [mL/min/1.73 m²] Follow-up eGFR N* (%) 98 (94.2) 103 (98.1) Mean(SD) [mL/min/1.73 m²] 42.99 (12.67) 45.39 (11.31) Mean change frombaseline (SD) 0.16 (9.14) 1.48 (6.70) [mL/min/1.73 m²]

In patients with type 2 diabetes and severe renal impairment, treatmentwith empagliflozin 25 mg at week 52 resulted in a small decrease ineGFR. However, at the 3-week follow-up visit mean eGFR increased to avalue slightly below baseline in the empagliflozin treatment group(Table 1C).

TABLE 1C Descriptive statistics for eGFR over time in patients withsevere renal impairment Empa Placebo 25 mg Number of patients N (%) 18(100.0) 21 (100.0) Baseline eGFR N* (%) 18 (100.0) 21 (100.0) Mean (SD)[mL/min/1.73 m²] 22.90 (3.44) 24.22 (3.99) End-of treatment eGFR N* (%)17 (94.4) 21 (100.0) Mean (SD) [mL/min/1.73 m²] 21.80 (6.36) 20.23(5.86) Mean change from baseline (SD) −1.17 (5.82) −3.98 (5.80)[mL/min/1.73 m²] Follow-up eGFR N* (%) 18 (100.0) 21 (100.0) Mean (SD)[mL/min/1.73 m²] 21.42 (6.58) 23.63 (7.40) Mean change from baseline(SD) −1.48 (6.03) −0.59 (6.76) [mL/min/1.73 m²]

Example 2 Empagliflozin in Hypertensive Patients with Type 2 DiabetesMellitus (T2DM)

A Phase III trial investigated the efficacy and safety of empagliflozin(EMPA) administered orally, once daily over 12 weeks in hypertensivepatients with T2DM (EMPA 10 or 25 mg, placebo (PBO)). Patients with asystolic blood pressure (SBP) of 130 to 159 mmHg and a diastolic bloodpressure (DSP) of 80 to 99 mmHg were included in the trial.

Treatment with empagliflozin 10 and 25 mg at week 12 resulted in a smalldecrease in eGFR. However, mean eGFR increased to a value slightly abovebaseline at the 2-week follow up visit in the empagliflozin treatmentgroups; in contrast, in the placebo group, mean eGFR remained slightlybelow baseline (Table 2).

TABLE 2 Descriptive statistics for eGFR (MDRD) over time Empa EmpaPlacebo 10 mg 25 mg Baseline eGFR N* (%) 238 (100) 241 (100) 244 (100)Mean (SD) 84.47 (17.06) 83.01 (16.43) 83.97 (17.85) [mL/min/1.73 m²]Last value on treatment eGFR N* (%) 237 (99.6) 238 (98.8) 240 (98.4)Mean (SD) 84.16 (17.95) 82.70 (17.11) 81.24 (17.61) [mL/min/1.73 m²]Mean change from −0.27 (9.18) −0.20 (8.99) −2.60 (9.98) baseline (SD)[mL/min/1.73 m²] Follow-up eGFR N* (%) 236 (99.2) 238 (98.8) 243 (99.6)Mean (SD) 83.52 (17.37) 86.25 (17.06) 86.60 (18.24) [mL/min/1.73 m²]Mean change from baseline (SD) [mL/min/1.73 m²] −0.82 (9.62) 3.06(10.05) 2.75 (9.71) N* (%) 236 (99.2) 236 (97.9) 239 (98.0) Mean changefrom last −0.52 (9.39) 3.32 (9.75) 5.54 (9.44) value on treatment (SD)[mL/min/1.73 m²] *Patients with values at this time point

Example 3 Empagliflozin in Patients with Type 2 Diabetes Mellitus (T2DM)Receiving Treatment with Basal Insulin

A Phase IIb trial investigated the efficacy and safety of empagliflozin(EMPA 10 or 25 mg, placebo (PBO)) administered orally, once daily over78 weeks in patients with T2DM receiving treatment with basal insulin(glargine, detemir, or NPH insulin only).

Treatment with empagliflozin 10 and 25 mg resulted in a small decreasein eGFR. However, mean eGFR increased to a value slightly below baselineat the 4-week follow up visit in the empagliflozin treatment groups; incontrast, in the placebo group, mean eGFR further slightly decreased(Table 3).

TABLE 3 Descriptive statistics for eGFR (MDRD) over time Empa EmpaPlacebo 10 mg 25 mg Number of patients, 170 (100.0) 169 (100.0) 155(100.0) N (%) Baseline eGFR N¹ (%) 170 (100.0) 169 (100.0) 155 (100.0)Mean (SD) 83.89 (22.73) 85.01 (23.63) 82.88 (25.46) Week 18 eGFR N¹ (%)134 (78.8) 133 (78.7) 113 (72.9) Mean (SD) 80.07 (20.15) 80.37 (23.03)79.11 (21.63) Mean change from −4.12 (12.27) −4.98 (11.40) −3.48 (10.10)baseline (SD) Week 54 eGFR N¹ (%) 106 (62.4) 106 (62.7) 97 (62.6) Mean(SD) 78.54 (21.06) 82.55 (23.60) 77.12 (23.59) Mean change from −4.88(10.85) −5.68 (14.36) −4.76 (11.05) baseline (SD) Week 78 eGFR N¹ (%)102 (60.0) 100 (59.2) 86 (55.5) Mean (SD) 78.52 (21.11) 81.86 (24.17)77.21 (20.68) Mean change from −5.27 (12.04) −5.52 (11.08) −5.64 (10.20)baseline (SD) eGFR at follow-up N¹ (%) 112 118 113 Mean (SD) 78.36(21.39) 83.74 (21.69) 81.35 (21.78) Mean change from −6.66 (12.06) −1.88(13.02) −0.79 (12.00) baseline (SD) ¹Percent of patient in populationwith values at this time point eGFR = estimated glomerular filtrationrate; MDRD = Modification of diet in renal disease; SD = standarddeviation

Example 4 Empagliflozin in Patients with Type 2 Diabetes Mellitus (T2DM)and Microalbuminuria and Macroalbuminuria

In a dedicated 52 week renal impairment study, patients were categorisedbased on their urine albumin/creatinine ratio (UACR) values at baseline,and 3 categories of patients were distinguished: patients with normalurine albumin/creatinine ratio values (<30 mg/g), patients withmicroalbuminuria (30 to <300 mg/g) and patients with macroalbuminurea(≧300 mg/g). Differences in mean changes from baseline between theplacebo and the empagliflozin treatment groups were noted for patientswith microalbuminuria or macroalbuminuria at baseline. For patients withmicroalbuminuria, mean urine albumin/creatinine ratio values increasedwith placebo treatment, remained nearly unchanged with empagliflozin 10mg treatment, and decreased with empagliflozin 25 mg treatment. Inpatients with macroalbuminuria at baseline, a decrease in mean urinealbumin/creatinine ratio was noted only in the empagliflozin groups;(Table 4A).

TABLE 4A Urine albumin-to-creatinine ratio (mg/g) by baseline urinealbumin-to-creatinine ratio at week 52 in normal patients and patientswith microalbuminuria and macroalbuminuria Change from baseline Microal-Macroal- Normal buminuria buminuria N Mean SD N Mean SD N Mean SDPlacebo 134 8.2 20.8 90 106.1 412.9 50 3.4 2050.5 Empag- 59 4.0 15.3 177.4 137.3 9 −716.3 1273.6 liflozin 10 mg Empag- 141 6.0 31.7 72 −39.493.8 61 −799.9 1543.7 liflozin 25 mg

Shifts between UACR categories at baseline and the end of treatment werenoted in the randomised treatment groups (Table 4B). A higher frequencyof patients in the empagliflozin treatment groups shifted from macro- ormicroalbuminura at baseline towards normal values and from macro- tomicroalbuminuria at the end of treatment. In addition, a higherproportion of patients in the placebo group shifted from normal valuesat baseline towards microalbuminuria at the end of treatment.

TABLE 4B Frequency of patients [N (%)] with shifts in urinealbumin-to-creatinine ratio (mg/g) at Week 52 relative to urinealbumin-to-creatinine ratio categories at baseline Last valueon-treatment Micro- Macro- Normal albuminuria albuminuria TreatmentBaseline N (%) N (%) N (%) Placebo Normal 118 (81.9) 26 (18.1)  0Microalbuminuria  22 (21.8) 67 (66.3) 12 (11.9) Macroalbuminuria  1(1.7)  6 (10.0) 53 (88.3) Empa 10 mg Normal  59 (89.4)  7 (10.6)  0Microalbuminuria  5 (27.8) 11 (61.1)  2 (11.1) Macroalbuminuria  1(11.1)  5 (55.6)  3 (33.3) Empa 25 mg Normal 135 (89.4) 16 (10.6)  0Microalbuminuria  19 (24.1) 57 (72.2)  3 (3.8) Macroalbuminuria  2 (2.7)22 (30.1) 49 (67.1) Categories for urine albumin-to-creatinine ratio:normal: <30 mg/g, microalbuminuria 30 to <300 mg/g, macroalbuminuria:≧300 mg/g

Example of Pharmaceutical Composition and Dosage Form

The following example of solid pharmaceutical compositions and dosageforms for oral administration serves to illustrate the present inventionmore fully without restricting it to the contents of the example.Further examples of compositions and dosage forms for oraladministration, are described in WO 2010/092126. The term “activesubstance” denotes empagliflozin according to this invention, especiallyits crystalline form as described in WO 2006/117359 and WO 2011/039107.

Tablets containing 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg of active substance2.5 mg/ 5 mg/ 10 mg/ 25 mg/ 50 mg/ per per per per per Active substancetablet tablet tablet tablet tablet Wet granulation active substance 2.5000  5.000  10.00  25.00  50.00 Lactose 40.6250  81.250 162.50113.00 226.00 Monohydrate Microcrystalline 12.5000  25.000  50.00  40.00 80.00 Cellulose Hydroxypropyl  1.8750  3.750  7.50  6.00  12.00Cellulose Croscarmellose  1.2500  2.500  5.00  4.00  8.00 SodiumPurified Water q.s. q.s. q.s. q.s. q.s. Dry Adds Microcrystalline 3.1250  6.250  12.50  10.00  20.00 Cellulose Colloidal silicon  0.3125 0.625  1.25  1.00  2.00 dioxide Magnesium stearate  0.3125  0.625  1.25 1.00  2.00 Total core 62.5000 125.000 250.00 200.00 400.00 Film CoatingFilm coating system  2.5000  4.000  7.00  6.00  9.00 Purified Water q.s.q.s. q.s. q.s. q.s. Total 65.000 129.000 257.00 206.00 409.00

Details regarding the manufacture of the tablets, the activepharmaceutical ingredient, the excipients and the film coating systemare described in WO 2010/092126, in particular in the Examples 5 and 6,which hereby is incorporated herein in its entirety.

1) A method of treating, preventing, protecting against, reducing therisk of, delaying the occurrence of and/or delaying the progression ofchronic kidney disease in a patient, said method comprisingadministering empagliflozin, optionally in combination with one or moreother therapeutic substances, to the patient. 2) The method according toclaim 1, wherein the progression of said chronic kidney disease is theprogression to end stage renal disease/kidney failure, or renal death inthe patient. 3) The method according to claim 1, wherein said patient isat risk for renal disease. 4) The method according to claim 1, whereinthe patient is a patient with prediabetes, type 1 or type 2 diabetesmellitus. 5) The method according to claim 1, wherein the patient has oris at risk of a cardiovascular disease. 6) The method according to claim1, wherein the patient is a patient with prediabetes, type 1 or type 2diabetes mellitus and with or at risk of a cardiovascular disease. 7) Amethod of treating, preventing, protecting against or delaying new onsetof albuminuria in a patient, said method comprising administeringempagliflozin, optionally in combination with one or more othertherapeutic substances, to the patient. 8) The method according to claim7, wherein said patient is at risk for renal disease. 9) The methodaccording to claim 7, wherein the patient is a patient with prediabetes,type 1 or type 2 diabetes mellitus. 10) The method according to claim 7,wherein the patient has or is at risk of a cardiovascular disease. 11)The method according to claim 7, wherein the patient is a patient withprediabetes, type 1 or type 2 diabetes mellitus and with or at risk of acardiovascular disease. 12) A method of treating, preventing, protectingagainst or delaying the progression from no albuminuria to micro- ormacroalbuminuria in a patient at risk for renal disease, said methodcomprising administering empagliflozin, optionally in combination withone or more other therapeutic substances, to the patient. 13) The methodaccording to claim 12, wherein the patient is a patient withprediabetes, type 1 or type 2 diabetes mellitus. 14) A method oftreating, preventing, protecting against or delaying the progressionfrom microalbuminuria to macroalbuminuria in a patient with chronickidney disease, said method comprising administering empagliflozin,optionally in combination with one or more other therapeutic substances,to the patient. 15) The method according to claim 14, wherein thepatient is a patient with prediabetes, type 1 or type 2 diabetesmellitus. 16) A method for treating, preventing, protecting against ordelaying the progression of chronic kidney disease in a patient, saidmethod administering empagliflozin, optionally in combination with oneor more other therapeutic substances, to the patient. 17) The methodaccording to claim 16, comprising preventing, protecting against ordelaying loss of eGFR, for example sustained eGFR loss of 50%, in saidpatient. 18) The method according to claim 16, wherein the patient is apatient with prediabetes, type 1 or type 2 diabetes mellitus. 19) Amethod of treating, preventing, protecting against or delaying theoccurrence of: new onset of albuminuria, doubling of serum creatininelevel accompanied by an eGFR (based on modification of diet in renaldisease (MDRD) formula) ≦45 mL/min/1.73 m², need for continuous renalreplacement therapy, or death due to renal disease, in a patient, saidmethod comprising administering empagliflozin, optionally in combinationwith one or more other therapeutic substances, to the patient. 20) Themethod according to claim 19, wherein the patient has chronic kidneydisease. 21) The method according to claim 19, wherein the patient is apatient with prediabetes, type 1 or type 2 diabetes mellitus. 22) Themethod according to claim 19, wherein the patient has or is at risk of acardiovascular disease. 23) The method according to claim 19, whereinthe patient is a patient with prediabetes, type 1 or type 2 diabetes andwith or at risk of a cardiovascular disease. 24) The method according toclaim 19, wherein the patient has chronic kidney disease and is apatient with prediabetes, type 1 or type 2 diabetes mellitus. 25) Themethod according to claim 1, wherein the patient is a patient with oneor more cardiovascular risk factors selected from A), B), C) and D): A)previous or existing vascular disease selected from myocardialinfarction, coronary artery disease, percutaneous coronary intervention,coronary artery by-pass grafting, ischemic or hemorrhagic stroke,congestive heart failure, and peripheral occlusive arterial disease, B)advanced age >1=60-70 years, and C) one or more cardiovascular riskfactors selected from advanced type 1 or type 2 diabetes mellitus >10years duration, hypertension, current daily cigarette smoking,dyslipidemia, obesity, age >/=40, metabolic syndrome, hyperinsulinemiaor insulin resistance, and hyperuricemia, erectile dysfunction,polycystic ovary syndrome, sleep apnea, or family history of vasculardisease or cardiomyopathy in first-degree relative; D) one or more ofthe following: confirmed history of myocardial infarction, unstableangina with documented multivessel coronary disease or positive stresstest, multivessel Percutaneous Coronary Intervention, multivesselCoronary Artery By-pass Grafting (CABG), history of ischemic orhemorrhagic stroke, peripheral occlusive arterial disease. 26) Themethod according to claim 1, wherein the one or more other therapeuticsubstances are selected from other antidiabetic substances. 27) Themethod according to claim 1, comprising administering empagliflozin incombination with metformin, with linagliptin or with metformin andlinagliptin. 28) The method according to claim 1, wherein the one ormore other therapeutic substances is a RAAS inhibitor. 29) The methodaccording to claim 1, wherein the one or more other therapeuticsubstances is a direct renin inhibitor, an Angiotensin-Converting Enzyme(ACE) inhibitor and/or an angiotensin II receptor blocker (ARB). 30) Themethod according to claim 1, comprising administering empagliflozin incombination with a RAAS inhibitor. 31) The method according to claim 1,comprising administering empagliflozin in combination with a directrenin inhibitor, an Angiotensin-Converting Enzyme (ACE) inhibitor and/oran angiotensin II receptor blocker (ARB). 32) The method according toclaim 1, wherein empagliflozin is administered orally in a total dailyamount of 10 mg or 25 mg. 33) The method according to claim 1, whereinempagliflozin is administered as a pharmaceutical composition comprising10 mg or 25 mg of empagliflozin.